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1.
Nat Commun ; 12(1): 1672, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33723266

RESUMEN

X-ray free-electron lasers (XFELs) enable obtaining novel insights in structural biology. The recently available MHz repetition rate XFELs allow full data sets to be collected in shorter time and can also decrease sample consumption. However, the microsecond spacing of MHz XFEL pulses raises new challenges, including possible sample damage induced by shock waves that are launched by preceding pulses in the sample-carrying jet. We explored this matter with an X-ray-pump/X-ray-probe experiment employing haemoglobin microcrystals transported via a liquid jet into the XFEL beam. Diffraction data were collected using a shock-wave-free single-pulse scheme as well as the dual-pulse pump-probe scheme. The latter, relative to the former, reveals significant degradation of crystal hit rate, diffraction resolution and data quality. Crystal structures extracted from the two data sets also differ. Since our pump-probe attributes were chosen to emulate EuXFEL operation at its 4.5 MHz maximum pulse rate, this prompts concern about such data collection.


Asunto(s)
Hemoglobinas/química , Hemoglobinas/efectos de la radiación , Inyecciones a Chorro/métodos , Rayos Láser , Cristalografía por Rayos X , Electrones , Humanos , Inyecciones a Chorro/instrumentación , Técnicas de Sonda Molecular , Rayos X
2.
Nat Commun ; 12(1): 1631, 2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712585

RESUMEN

Nicotinamide adenine dinucleotide (NAD) is a key molecule in cellular bioenergetics and signalling. Various bacterial pathogens release NADase enzymes into the host cell that deplete the host's NAD+ pool, thereby causing rapid cell death. Here, we report the identification of NADases on the surface of fungi such as the pathogen Aspergillus fumigatus and the saprophyte Neurospora crassa. The enzymes harbour a tuberculosis necrotizing toxin (TNT) domain and are predominately present in pathogenic species. The 1.6 Å X-ray structure of the homodimeric A. fumigatus protein reveals unique properties including N-linked glycosylation and a Ca2+-binding site whose occupancy regulates activity. The structure in complex with a substrate analogue suggests a catalytic mechanism that is distinct from those of known NADases, ADP-ribosyl cyclases and transferases. We propose that fungal NADases may convey advantages during interaction with the host or competing microorganisms.


Asunto(s)
Proteínas Fúngicas/química , Proteínas Fúngicas/aislamiento & purificación , Proteínas Fúngicas/metabolismo , NAD+ Nucleosidasa/química , NAD+ Nucleosidasa/aislamiento & purificación , NAD+ Nucleosidasa/metabolismo , ADP-Ribosil Ciclasa/metabolismo , Animales , Aspergillus fumigatus/enzimología , Aspergillus fumigatus/genética , Aspergillus fumigatus/metabolismo , Aspergillus fumigatus/patogenicidad , Cristalografía por Rayos X , Proteínas Fúngicas/genética , Regulación Fúngica de la Expresión Génica , Proteínas de la Membrana/química , Proteínas de la Membrana/aislamiento & purificación , Proteínas de la Membrana/metabolismo , Modelos Moleculares , NAD/metabolismo , NAD+ Nucleosidasa/genética , Neurospora crassa/enzimología , Neurospora crassa/genética , Neurospora crassa/metabolismo , Neurospora crassa/patogenicidad , Conformación Proteica , Células Sf9 , Transducción de Señal
3.
Nat Commun ; 12(1): 1677, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33723253

RESUMEN

The seven 14-3-3 isoforms are highly abundant human proteins encoded by similar yet distinct genes. 14-3-3 proteins recognize phosphorylated motifs within numerous human and viral proteins. Here, we analyze by X-ray crystallography, fluorescence polarization, mutagenesis and fusicoccin-mediated modulation the structural basis and druggability of 14-3-3 binding to four E6 oncoproteins of tumorigenic human papillomaviruses. 14-3-3 isoforms bind variant and mutated phospho-motifs of E6 and unrelated protein RSK1 with different affinities, albeit following an ordered affinity ranking with conserved relative KD ratios. Remarkably, 14-3-3 isoforms obey the same hierarchy when binding to most of their established targets, as supported by literature and a recent human complexome map. This knowledge allows predicting proportions of 14-3-3 isoforms engaged with phosphoproteins in various tissues. Notwithstanding their individual functions, cellular concentrations of 14-3-3 may be collectively adjusted to buffer the strongest phosphorylation outbursts, explaining their expression variations in different tissues and tumors.


Asunto(s)
Proteínas 14-3-3/química , Isoformas de Proteínas , Proteínas 14-3-3/metabolismo , Secuencia de Aminoácidos , Cristalografía por Rayos X , Humanos , Papillomaviridae , Fosfoproteínas , Fosforilación , Unión Proteica , Isoformas de Proteínas/metabolismo
4.
Nat Commun ; 12(1): 1859, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767140

RESUMEN

Biogenesis of eukaryotic box C/D small nucleolar ribonucleoproteins initiates co-transcriptionally and requires the action of the assembly machinery including the Hsp90/R2TP complex, the Rsa1p:Hit1p heterodimer and the Bcd1 protein. We present genetic interactions between the Rsa1p-encoding gene and genes involved in chromatin organization including RTT106 that codes for the H3-H4 histone chaperone Rtt106p controlling H3K56ac deposition. We show that Bcd1p binds Rtt106p and controls its transcription-dependent recruitment by reducing its association with RNA polymerase II, modulating H3K56ac levels at gene body. We reveal the 3D structures of the free and Rtt106p-bound forms of Bcd1p using nuclear magnetic resonance and X-ray crystallography. The interaction is also studied by a combination of biophysical and proteomic techniques. Bcd1p interacts with a region that is distinct from the interaction interface between the histone chaperone and histone H3. Our results are evidence for a protein interaction interface for Rtt106p that controls its transcription-associated activity.


Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Chaperonas Moleculares/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Activación Transcripcional/fisiología , Proliferación Celular/fisiología , Cromatina/genética , Cristalografía por Rayos X , Histonas/metabolismo , Resonancia Magnética Nuclear Biomolecular , ARN Polimerasa II/metabolismo , Ribonucleoproteínas Nucleolares Pequeñas/genética , Ribonucleoproteínas Nucleolares Pequeñas/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Ribosomas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Transcripción Genética/genética
5.
Nat Commun ; 12(1): 1762, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741910

RESUMEN

Time-resolved studies of biomacromolecular crystals have been limited to systems involving only minute conformational changes within the same lattice. Ligand-induced changes greater than several angstroms, however, are likely to result in solid-solid phase transitions, which require a detailed understanding of the mechanistic interplay between conformational and lattice transitions. Here we report the synchronous behavior of the adenine riboswitch aptamer RNA in crystal during ligand-triggered isothermal phase transitions. Direct visualization using polarized video microscopy and atomic force microscopy shows that the RNA molecules undergo cooperative rearrangements that maintain lattice order, whose cell parameters change distinctly as a function of time. The bulk lattice order throughout the transition is further supported by time-resolved diffraction data from crystals using an X-ray free electron laser. The synchronous molecular rearrangements in crystal provide the physical basis for studying large conformational changes using time-resolved crystallography and micro/nanocrystals.


Asunto(s)
Conformación de Ácido Nucleico , Transición de Fase , ARN/química , Riboswitch , Adenina/química , Aptámeros de Nucleótidos/química , Cristalografía por Rayos X , Microscopía de Fuerza Atómica/métodos , Microscopía de Polarización/métodos , Modelos Moleculares , Imagen de Lapso de Tiempo/métodos
6.
Nat Commun ; 12(1): 1728, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741927

RESUMEN

Microsomal glutathione S-transferase 2 (MGST2) produces leukotriene C4, key for intracrine signaling of endoplasmic reticulum (ER) stress, oxidative DNA damage and cell death. MGST2 trimer restricts catalysis to only one out of three active sites at a time, but the molecular basis is unknown. Here, we present crystal structures of human MGST2 combined with biochemical and computational evidence for a concerted mechanism, involving local unfolding coupled to global conformational changes that regulate catalysis. Furthermore, synchronized changes in the biconical central pore modulate the hydrophobicity and control solvent influx to optimize reaction conditions at the active site. These unique mechanistic insights pertain to other, structurally related, drug targets.


Asunto(s)
Glutatión Transferasa/química , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Sitios de Unión , Catálisis , Dominio Catalítico , Cristalografía por Rayos X , Retículo Endoplásmico/metabolismo , Humanos , Leucotrieno C4/metabolismo , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Estrés Oxidativo , Conformación Proteica
7.
Nat Commun ; 12(1): 1538, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750786

RESUMEN

Plasmodium vivax preferentially invades reticulocytes and recognition of these cells is mediated by P. vivax Reticulocyte Binding Protein 2b (PvRBP2b) binding to human Transferrin receptor 1 (TfR1) and Transferrin (Tf). Longitudinal cohort studies in Papua New Guinea, Thailand and Brazil show that PvRBP2b antibodies are correlated with protection against P. vivax infection and disease. Here, we isolate and characterize anti-PvRBP2b human monoclonal antibodies from two individuals in Cambodia with natural P. vivax infection. These antibodies bind with high affinities and map to different regions of PvRBP2b. Several human antibodies block PvRBP2b binding to reticulocytes and inhibit complex formation with human TfR1-Tf. We describe different structural mechanisms for functional inhibition, including either steric hindrance with TfR1-Tf or the reticulocyte membrane. These results show that naturally acquired human antibodies against PvRBP2b can inhibit its function which is important for P. vivax invasion.


Asunto(s)
Anticuerpos Bloqueadores , Anticuerpos Monoclonales/inmunología , Proteínas de la Membrana/metabolismo , Plasmodium vivax/metabolismo , Proteínas Protozoarias/metabolismo , Reticulocitos/metabolismo , Anticuerpos Antiprotozoarios/inmunología , Antígenos CD , Antígenos de Protozoos/química , Antígenos de Protozoos/genética , Antígenos de Protozoos/inmunología , Cambodia , Cristalografía por Rayos X , Humanos , Estudios Longitudinales , Malaria Vivax/inmunología , Malaria Vivax/parasitología , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Modelos Moleculares , Plasmodium vivax/genética , Proteínas Protozoarias/química , Proteínas Protozoarias/genética , Receptores de Transferrina
8.
Nat Commun ; 12(1): 1530, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750792

RESUMEN

De novo protein design is advancing rapidly. However, most designs are for single states. Here we report a de novo designed peptide that forms multiple α-helical-bundle states that are accessible and interconvertible under the same conditions. Usually in such designs amphipathic α helices associate to form compact structures with consolidated hydrophobic cores. However, recent rational and computational designs have delivered open α-helical barrels with functionalisable cavities. By placing glycine judiciously in the helical interfaces of an α-helical barrel, we obtain both open and compact states in a single protein crystal. Molecular dynamics simulations indicate a free-energy landscape with multiple and interconverting states. Together, these findings suggest a frustrated system in which steric interactions that maintain the open barrel and the hydrophobic effect that drives complete collapse are traded-off. Indeed, addition of a hydrophobic co-solvent that can bind within the barrel affects the switch between the states both in silico and experimentally.


Asunto(s)
Péptidos/química , Cristalografía por Rayos X , Interacciones Hidrofóbicas e Hidrofílicas , Simulación de Dinámica Molecular , Conformación Proteica , Conformación Proteica en Hélice alfa , Ingeniería de Proteínas , Proteínas/química , Solventes
9.
J Enzyme Inhib Med Chem ; 36(1): 727-736, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33685335

RESUMEN

The novel coronavirus disease COVID-19, caused by the virus SARS CoV-2, has exerted a significant unprecedented economic and medical crisis, in addition to its impact on the daily life and health care systems all over the world. Regrettably, no vaccines or drugs are currently available for this new critical emerging human disease. Joining the global fight against COVID-19, in this study we aim at identifying a potential novel inhibitor for SARS COV-2 2'-O-methyltransferase (nsp16) which is one of the most attractive targets in the virus life cycle, responsible for the viral RNA protection via a cap formation process. Firstly, nsp16 enzyme bound to Sinefungin was retrieved from the protein data bank (PDB ID: 6WKQ), then, a 3D pharmacophore model was constructed to be applied to screen 48 Million drug-like compounds of the Zinc database. This resulted in only 24 compounds which were subsequently docked into the enzyme. The best four score-ordered hits from the docking outcome exhibited better scores compared to Sinefungin. Finally, three molecular dynamics (MD) simulation experiments for 150 ns were carried out as a refinement step for our proposed approach. The MD and MM-PBSA outputs revealed compound 11 as the best potential nsp16 inhibitor herein identified, as it displayed a better stability and average binding free energy for the ligand-enzyme complex compared to Sinefungin.


Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Proteínas no Estructurales Virales/química , Adenosina/análogos & derivados , Adenosina/química , Adenosina/metabolismo , Antivirales/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Bases de Datos Farmacéuticas , Bases de Datos de Proteínas , Estabilidad de Medicamentos , Inhibidores Enzimáticos/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Cinética , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Termodinámica , Proteínas no Estructurales Virales/antagonistas & inhibidores
10.
Molecules ; 26(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672721

RESUMEN

The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002-2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PLpro inhibitor co-crystallised with the recently solved SARS-CoV-2 PLpro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PLpro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PLpro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PLpro, which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and eliminate those with undesirable properties. Overall, we present four novel, and lipophilic, scaffolds obtained from an exhaustive search of diverse and uncharted regions of chemical space, which may be further explored in vitro through structure-activity relationship (SAR) studies in the search for more potent inhibitors. Furthermore, these scaffolds were predicted to have fewer off-target interactions than GRL-0617. Lastly, to our knowledge, this work contains the largest ligand-based virtual screen performed against GRL-0617.


Asunto(s)
Antivirales/química , Inhibidores de Cisteína Proteinasa/química , Simulación del Acoplamiento Molecular , /enzimología , Antivirales/uso terapéutico , /antagonistas & inhibidores , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos
11.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652868

RESUMEN

Three new 3D metal-organic porous frameworks based on Co(II) and 2,2'-bithiophen-5,5'-dicarboxylate (btdc2-) [Co3(btdc)3(bpy)2]·4DMF, 1; [Co3(btdc)3(pz)(dmf)2]·4DMF·1.5H2O, 2; [Co3(btdc)3(dmf)4]∙2DMF∙2H2O, 3 (bpy = 2,2'-bipyridyl, pz = pyrazine, dmf = N,N-dimethylformamide) were synthesized and structurally characterized. All compounds share the same trinuclear carboxylate building units {Co3(RCOO)6}, connected either by btdc2- ligands (1, 3) or by both btdc2- and pz bridging ligands (2). The permanent porosity of 1 was confirmed by N2, O2, CO, CO2, CH4 adsorption measurements at various temperatures (77 K, 273 K, 298 K), resulted in BET surface area 667 m2⋅g-1 and promising gas separation performance with selectivity factors up to 35.7 for CO2/N2, 45.4 for CO2/O2, 20.8 for CO2/CO, and 4.8 for CO2/CH4. The molar magnetic susceptibilities χp(T) were measured for 1 and 2 in the temperature range 1.77-330 K at magnetic fields up to 10 kOe. The room-temperature values of the effective magnetic moments for compounds 1 and 2 are µeff (300 K) ≈ 4.93 µB. The obtained results confirm the mainly paramagnetic nature of both compounds with some antiferromagnetic interactions at low-temperatures T < 20 K in 2 between the Co(II) cations separated by short pz linkers. Similar conclusions were also derived from the field-depending magnetization data of 1 and 2.


Asunto(s)
Cobalto/química , Estructuras Metalorgánicas/ultraestructura , Conformación Molecular , Compuestos Organometálicos/química , Adsorción/efectos de los fármacos , Cristalografía por Rayos X , Ligandos , Fenómenos Magnéticos , Estructuras Metalorgánicas/química , Porosidad , Propiedades de Superficie
12.
PLoS Pathog ; 17(3): e1009328, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33657135

RESUMEN

A key step to the SARS-CoV-2 infection is the attachment of its Spike receptor-binding domain (S RBD) to the host receptor ACE2. Considerable research has been devoted to the development of neutralizing antibodies, including llama-derived single-chain nanobodies, to target the receptor-binding motif (RBM) and to block ACE2-RBD binding. Simple and effective strategies to increase potency are desirable for such studies when antibodies are only modestly effective. Here, we identify and characterize a high-affinity synthetic nanobody (sybody, SR31) as a fusion partner to improve the potency of RBM-antibodies. Crystallographic studies reveal that SR31 binds to RBD at a conserved and 'greasy' site distal to RBM. Although SR31 distorts RBD at the interface, it does not perturb the RBM conformation, hence displaying no neutralizing activities itself. However, fusing SR31 to two modestly neutralizing sybodies dramatically increases their affinity for RBD and neutralization activity against SARS-CoV-2 pseudovirus. Our work presents a tool protein and an efficient strategy to improve nanobody potency.


Asunto(s)
/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos de Dominio Único/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/genética , Anticuerpos Antivirales/química , Anticuerpos Antivirales/genética , Afinidad de Anticuerpos , Sitios de Unión , Cristalografía por Rayos X , Células HEK293 , Humanos , Modelos Moleculares , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/genética
13.
Comput Biol Med ; 131: 104295, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33662683

RESUMEN

Papain-Like Protease (PLpro) is a key protein for SARS-CoV-2 viral replication which is the cause of the emerging COVID-19 pandemic. Targeting PLpro can suppress viral replication and provide treatment options for COVID-19. Due to the dynamic nature of its binding site loop, PLpro multiple conformations were generated through a long-range 1 micro-second molecular dynamics (MD) simulation. Clustering the MD trajectory enabled us to extract representative structures for the conformational space generated. Adding to the MD representative structures, X-ray structures were involved in an ensemble docking approach to screen the FDA approved drugs for a drug repositioning endeavor. Guided by our recent benchmarking study of SARS-CoV-2 PLpro, FRED docking software was selected for such a virtual screening task. The results highlighted potential consensus binders to many of the MD clusters as well as the newly introduced X-ray structure of PLpro complexed with a small molecule. For instance, three drugs Benserazide, Dobutamine and Masoprocol showed a superior consensus enrichment against the PLpro conformations. Further MD simulations for these drugs complexed with PLpro suggested the superior stability and binding of dobutamine and masoprocol inside the binding site compared to Benserazide. Generally, this approach can facilitate identifying drugs for repositioning via targeting multiple conformations of a crucial target for the rapidly emerging COVID-19 pandemic.


Asunto(s)
Inhibidores de Cisteína Proteinasa/química , Reposicionamiento de Medicamentos , Simulación de Dinámica Molecular , /enzimología , Sitios de Unión , /química , Cristalografía por Rayos X , Estabilidad de Enzimas , Humanos
14.
Molecules ; 26(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33671921

RESUMEN

Coinage metal(I)···metal(I) interactions are widely of interest in fields such as supramolecular assembly and unique luminescent properties, etc. Only two types of polynuclear silver(I) pyrazolato complexes have been reported, however, and no detailed spectroscopic characterizations have been reported. An unexpected synthetic method yielded a polynuclear silver(I) complex [Ag(µ-L1Clpz)]n (L1Clpz- = 4-chloride-3,5-diisopropyl-1-pyrazolate anion) by the reaction of {[Ag(µ-L1Clpz)]3}2 with (nBu4N)[Ag(CN)2]. The obtained structure was compared with the known hexanuclear silver(I) complex {[Ag(µ-L1Clpz)]3}2. The Ag···Ag distances in [Ag(µ-L1Clpz)]n are slightly shorter than twice Bondi's van der Waals radius, indicating some Ag···Ag argentophilic interactions. Two Ag-N distances in [Ag(µ-L1Clpz)]n were found: 2.0760(13) and 2.0716(13) Å, and their N-Ag-N bond angles of 180.00(7)° and 179.83(5)° indicate that each silver(I) ion is coordinated by two pyrazolyl nitrogen atoms with an almost linear coordination. Every five pyrazoles point in the same direction to form a 1-D zig-zag structure. Some spectroscopic properties of [Ag(µ-L1Clpz)]n in the solid-state are different from those of {[Ag(µ-L1Clpz)]3}2 (especially in the absorption and emission spectra), presumably attributable to this zig-zag structure having longer but differently arranged intramolecular Ag···Ag interactions of 3.39171(17) Å. This result clearly demonstrates the different physicochemical properties in the solid-state between 1-D coordination polymer and metalacyclic trinuclear (hexanuclear) or tetranuclear silver(I) pyrazolate complexes.


Asunto(s)
Polímeros/síntesis química , Pirazoles/síntesis química , Plata/química , Cristalografía por Rayos X , Luminiscencia , Conformación Molecular , Polímeros/química , Pirazoles/química , Espectrofotometría Ultravioleta , Temperatura
15.
Molecules ; 26(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33672016

RESUMEN

Reaction of 2,2'-bipyridine (2,2'-bipy) or 1,10-phenantroline (phen) with [Mn(Piv)2(EtOH)]n led to the formation of binuclear complexes [Mn2(Piv)4L2] (L = 2,2'-bipy (1), phen (2); Piv- is the anion of pivalic acid). Oxidation of 1 or 2 by air oxygen resulted in the formation of tetranuclear MnII/III complexes [Mn4O2(Piv)6L2] (L = 2,2'-bipy (3), phen (4)). The hexanuclear complex [Mn6(OH)2(Piv)10(pym)4] (5) was formed in the reaction of [Mn(Piv)2(EtOH)]n with pyrimidine (pym), while oxidation of 5 produced the coordination polymer [Mn6O2(Piv)10(pym)2]n (6). Use of pyrazine (pz) instead of pyrimidine led to the 2D-coordination polymer [Mn4(OH)(Piv)7(µ2-pz)2]n (7). Interaction of [Mn(Piv)2(EtOH)]n with FeCl3 resulted in the formation of the hexanuclear complex [MnII4FeIII2O2(Piv)10(MeCN)2(HPiv)2] (8). The reactions of [MnFe2O(OAc)6(H2O)3] with 4,4'-bipyridine (4,4'-bipy) or trans-1,2-(4-pyridyl)ethylene (bpe) led to the formation of 1D-polymers [MnFe2O(OAc)6L2]n·2nDMF, where L = 4,4'-bipy (9·2DMF), bpe (10·2DMF) and [MnFe2O(OAc)6(bpe)(DMF)]n·3.5nDMF (11·3.5DMF). All complexes were characterized by single-crystal X-ray diffraction. Desolvation of 11·3.5DMF led to a collapse of the porous crystal lattice that was confirmed by PXRD and N2 sorption measurements, while alcohol adsorption led to porous structure restoration. Weak antiferromagnetic exchange was found in the case of binuclear MnII complexes (JMn-Mn = -1.03 cm-1 for 1 and 2). According to magnetic data analysis (JMn-Mn = -(2.69 ÷ 0.42) cm-1) and DFT calculations (JMn-Mn = -(6.9 ÷ 0.9) cm-1) weak antiferromagnetic coupling between MnII ions also occurred in the tetranuclear {Mn4(OH)(Piv)7} unit of the 2D polymer 7. In contrast, strong antiferromagnetic coupling was found in oxo-bridged trinuclear fragment {MnFe2O(OAc)6} in 11·3.5DMF (JFe-Fe = -57.8 cm-1, JFe-Mn = -20.12 cm-1).


Asunto(s)
Acetatos/química , Complejos de Coordinación/química , Compuestos Heterocíclicos/química , Manganeso/química , Valeratos/química , Adsorción , Complejos de Coordinación/síntesis química , Cristalografía por Rayos X , Espectroscopía de Resonancia por Spin del Electrón , Fenómenos Magnéticos , Conformación Molecular , Temperatura , Termogravimetría , Valeratos/síntesis química , Difracción de Rayos X
16.
Nat Commun ; 12(1): 1570, 2021 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-33692357

RESUMEN

The ULK complex initiates the autophagosome formation, and has recently been implicated in selective autophagy by interacting with autophagy receptors through its FIP200 subunit. However, the structural mechanism underlying the interactions of autophagy receptors with FIP200 and the relevant regulatory mechanism remain elusive. Here, we discover that the interactions of FIP200 Claw domain with autophagy receptors CCPG1 and Optineurin can be regulated by the phosphorylation in their respective FIP200-binding regions. We determine the crystal structures of FIP200 Claw in complex with the phosphorylated CCPG1 and Optineurin, and elucidate the detailed molecular mechanism governing the interactions of FIP200 Claw with CCPG1 and Optineurin as well as their potential regulations by kinase-mediated phosphorylation. In addition, we define the consensus FIP200 Claw-binding motif, and find other autophagy receptors that contain this motif within their conventional LC3-interacting regions. In all, our findings uncover a general and phosphoregulatable binding mode shared by many autophagy receptors to interact with FIP200 Claw for autophagosome biogenesis, and are valuable for further understanding the molecular mechanism of selective autophagy.


Asunto(s)
Proteínas Relacionadas con la Autofagia/química , Proteínas Relacionadas con la Autofagia/metabolismo , Autofagia/fisiología , Secuencias de Aminoácidos , Animales , Cromatografía en Gel , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Fosforilación , Unión Proteica , Células Sf9
17.
Molecules ; 26(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33669118

RESUMEN

The goal of the work reported here was to amplify the fluorescent properties of 4-aryliden-5(4H)-oxazolones by suppression of the hula-twist non-radiative deactivation pathway. This aim was achieved by simultaneous bonding of a Pd center to the N atom of the heterocycle and the ortho carbon of the arylidene ring. Two different 4-((Z)-arylidene)-2-((E)-styryl)-5(4H)-oxazolones, the structures of which are closely related to the chromophore of the Kaede protein and substituted at the 2- and 4-positions of the arylidene ring (1a OMe; 1b F), were used as starting materials. Oxazolones 1a and 1b were reacted with Pd(OAc)2 to give the corresponding dinuclear orthometalated palladium derivates 2a and 2b by regioselective C-H activation of the ortho-position of the arylidene ring. Reaction of 2a (2b) with LiCl promoted the metathesis of the bridging carboxylate by chloride ligands to afford dinuclear 3a (3b). Mononuclear complexes containing the orthopalladated oxazolone and a variety of ancillary ligands (acetylacetonate (4a, 4b), hydroxyquinolinate (5a), aminoquinoline (6a), bipyridine (7a), phenanthroline (8a)) were prepared from 3a or 3b through metathesis of anionic ligands or substitution of neutral weakly bonded ligands. All species were fully characterized and the X-ray determination of the molecular structure of 7a was carried out. This structure has strongly distorted ligands due to intramolecular interactions. Fluorescence measurements showed an increase in the quantum yield (QY) by up to one order of magnitude on comparing the free oxazolone (QY < 1%) with the palladated oxazolone (QY = 12% for 6a). This fact shows that the coordination of the oxazolone to the palladium efficiently suppresses the hula-twist deactivation pathway.


Asunto(s)
Complejos de Coordinación/química , Colorantes Fluorescentes/química , Proteínas Luminiscentes/química , Oxazolona/química , Paladio/química , Complejos de Coordinación/síntesis química , Cristalografía por Rayos X , Colorantes Fluorescentes/síntesis química , Modelos Moleculares , Estructura Molecular
18.
Molecules ; 26(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33669147

RESUMEN

An aniline-functionalized naphthalene dialdehyde Schiff base fluorescent probe L with aggregation-induced enhanced emission (AIEE) characteristics was synthesized via a simple one-step condensation reaction and exhibited excellent sensitivity and selectivity towards copper(II) ions in aqueous media with a fluorescence " turn-off " phenomenon. The detection limit of the probe is 1.64 × 10-8 mol·L-1. Furthermore, according to the results of the UV-vis/fluorescence titrations, Job's plot method and 1H-NMR titrations, a 1:2 stoichiometry was identified. The binding constant between L and Cu2+ was calculated to be Ka = 1.222 × 103. In addition, the AIEE fluorescent probe L could be applied to detection in real water samples with satisfactory recoveries in the range 99.10-102.90% in lake water and 98.49-102.37% in tap water.


Asunto(s)
Cobre/análisis , Colorantes Fluorescentes/química , Naftalenos/química , Contaminantes Químicos del Agua/análisis , Cristalografía por Rayos X , Colorantes Fluorescentes/síntesis química , Iones/análisis , Modelos Moleculares , Estructura Molecular , Naftalenos/síntesis química , Bases de Schiff/síntesis química , Bases de Schiff/química
19.
Molecules ; 26(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669754

RESUMEN

Functional molecule-based solids built of metal complexes can reveal a great impact of external stimuli upon their optical, magnetic, electric, and mechanical properties. We report a novel molecular material, {[EuIII(H2O)3(pyrone)4][CoIII(CN)6]}·nH2O (1, n = 2; 2, n = 1), which was obtained by the self-assembly of Eu3+ and [Co(CN)6]3- ions in the presence of a small 2-pyrrolidinone (pyrone) ligand in an aqueous medium. The as-synthesized material, 1, consists of dinuclear cyanido-bridged {EuCo} molecules accompanied by two H-bonded water molecules. By lowering the relative humidity (RH) below 30% at room temperature, 1 undergoes a single-crystal-to-single-crystal transformation related to the partial removal of crystallization water molecules which results in the new crystalline phase, 2. Both 1 and 2 solvates exhibit pronounced EuIII-centered visible photoluminescence. However, they differ in the energy splitting of the main emission band of a 5D0 → 7F2 origin, and the emission lifetime, which is longer in the partially dehydrated 2. As the 1 ↔ 2 structural transformation can be repeatedly reversed by changing the RH value, the reported material shows a room-temperature switching of detailed luminescent features including the ratio between emission components and the emission lifetime values.


Asunto(s)
Complejos de Coordinación/química , Humedad , Luminiscencia , Cristalografía por Rayos X , Modelos Moleculares , Temperatura
20.
Molecules ; 26(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670480

RESUMEN

One-pot reaction of the Schiff base N,N'-ethylene bis(salicylaldimine) (H2L), CoCl2.6H2O, and [Ph2SnCl2] in acetone produces the mixed valence CoIICoIII2 compound [CoIICoIII2(µ-L)2(Ph)2(µ-Cl)2]·(CH3)2CO·H2O (1). Our recent study already revealed that the same reaction mixtures in methanol or ethanol produced a heterometallic SnIVCoIII (2) or monometallic CoIII complex (3), respectively. Comparison of these organometallic systems shows that the 2,1-intermetallic Ph shift occurs in any of those solvents, but their relevant structural features (mononuclear, dinuclear-heterometallic, and trinuclear mixed valence) are solvent dependent. Geometrical structural rotation is also discussed among the related organometallic CoIICoIII2 systems. The AC magnetic susceptibility measurements indicate that 1 is a single molecule magnet (SMM), exhibiting a field-induced slow magnetic relaxation with two modes. The relaxation time for the low-frequency channel is as slow as τ~0.6 s at T = 2.0 K and BDC = 1.0 T.


Asunto(s)
Cobalto/química , Imanes/química , Solventes/química , Cristalografía por Rayos X , Electricidad , Campos Magnéticos , Conformación Molecular , Rotación , Temperatura
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