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1.
Acta Crystallogr D Struct Biol ; 76(Pt 4): 385-399, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32254063

RESUMO

In processing X-ray diffraction data, the intensities obtained from integration of the diffraction images must be corrected for experimental effects in order to place all intensities on a common scale both within and between data collections. Scaling corrects for effects such as changes in sample illumination, absorption and, to some extent, global radiation damage that cause the measured intensities of symmetry-equivalent observations to differ throughout a data set. This necessarily requires a prior evaluation of the point-group symmetry of the crystal. This paper describes and evaluates the scaling algorithms implemented within the DIALS data-processing package and demonstrates the effectiveness and key features of the implementation on example macromolecular crystallographic rotation data. In particular, the scaling algorithms enable new workflows for the scaling of multi-crystal or multi-sweep data sets, providing the analysis required to support current trends towards collecting data from ever-smaller samples. In addition, the implementation of a free-set validation method is discussed, which allows the quantification of the suitability of scaling-model and algorithm choices.


Assuntos
Algoritmos , Cristalografia por Raios X , Software , Difração de Raios X , Substâncias Macromoleculares
2.
Chemosphere ; 251: 126395, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32155498

RESUMO

Deoxynucleotides can be good monomers for arsenite ion-imprinted polymers (IIPs) due to the successful obtainment of aptamers which can specifically recognize arsenite. However, the recognition and interaction mechanism between arsenite and deoxynucleotides is still not clear. In this work, the binding interactions between arsenite and deoxynucleotides (dAMP, dTMP, dGMP, dCMP) as pH changing from 1 to 14 were investigated using density functional theory calculations as well as spectroscopy analysis. dGMP was calculated to have the largest affinity towards arsenite. H3AsO30-dGMP0 binding at phosphate group, H3AsO30-dAMP2-, H3AsO30-dCMP0 and H3AsO30-dTMP2- binding around nucleobase were found to be the most stable complexes. This suggests the optimal pH ranges for binding interactions of dAMP, dCMP, dGMP and dTMP towards arsenite might be 6.10-9.23, 1.00-4.50, 1.00-2.40 and 6.40-9.23, respectively, which agree with UV/VIS experimental results. Reduced Density Gradient method indicated that the binding interactions of arsenite with deoxynucleotides are mainly attributed to hydrogen bonds (H-bond). The strengths of these H-bonds are affected by pH. FT-IR and NMR spectroscopy analysis also provided essential H-bonding information, giving direct evidence to support the computational conclusions.


Assuntos
Arsenitos/química , Modelos Químicos , Nucleotídeos de Desoxiguanina , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Substâncias Macromoleculares/química , Espectroscopia de Infravermelho com Transformada de Fourier
3.
Nat Methods ; 17(4): 395-398, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32152501

RESUMO

We demonstrate single-particle charge detection mass spectrometry on an Orbitrap for the analysis of megadalton biomolecular assemblies. We establish that the signal amplitudes of individual ions scale linearly with their charge, which can be used to resolve mixed ion populations, determine charge states and thus also determine the masses of individual ions. This enables the ultrasensitive analysis of heterogeneous protein assemblies including immunoglobulin oligomers, ribosomes, proteinaceous nanocontainers and genome-packed adeno-associated viruses.


Assuntos
Substâncias Macromoleculares/química , Espectrometria de Massas/métodos , Sensibilidade e Especificidade
4.
Artigo em Inglês | MEDLINE | ID: mdl-32145639

RESUMO

Destruction of assembly structures has been identified as a major cause for activity loss of virus and virus-like particles during their chromatographic process. A deep insight into the denaturation process at the solid-liquid interfaces is important for rational design of purification. In this study, in-situ differential scanning calorimetry (DSC) was employed to study the dissociation process of inactivated foot-and-mouth disease virus (FMDV) during ion exchange chromatography (IEC) at different levels of pH. The intact FMDV known as 146S and the dissociation products were quantified by high performance size exclusion chromatography (HPSEC) and the thermo-stability of 146S on-column was monitored in-situ by DSC. Serious dissociation was found at pH 7.0 and pH 8.0, leading to low 146S recoveries of 12.3% and 43.7%, respectively. The elution profiles from IEC and HPSEC combined with the thermal transition temperatures of 146S dissociation (Tm1) from DSC suggested two denaturation mechanisms that the 146S dissociation occurred on-column after adsorption at pH 7.0 and during elution step at pH 8.0. By appending different excipients including sucrose, the improvement of 146S recovery and reduced dissociation was found highly correlated to increment of 146S stability on-column detected by DSC. The highest recovery of 99.9% and the highest Tm1 of 54.49 °C were obtained at pH 9.0 with 20% (w/v) sucrose. According to chromatographic behaviors and Tm1, three different dissociation processes in IEC were discussed. The study provides a perspective to understand the denaturation process of assemblies during chromatography, and also supplies a strategy to improve assembly recovery.


Assuntos
Vírus da Febre Aftosa/química , Substâncias Macromoleculares/química , Adsorção , Cromatografia em Gel , Cromatografia por Troca Iônica , Humanos , Concentração de Íons de Hidrogênio , Transição de Fase , Propriedades de Superfície , Temperatura de Transição
5.
Nat Commun ; 11(1): 876, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054835

RESUMO

Cryo electron tomography with subsequent subtomogram averaging is a powerful technique to structurally analyze macromolecular complexes in their native context. Although close to atomic resolution in principle can be obtained, it is not clear how individual experimental parameters contribute to the attainable resolution. Here, we have used immature HIV-1 lattice as a benchmarking sample to optimize the attainable resolution for subtomogram averaging. We systematically tested various experimental parameters such as the order of projections, different angular increments and the use of the Volta phase plate. We find that although any of the prominently used acquisition schemes is sufficient to obtain subnanometer resolution, dose-symmetric acquisition provides considerably better outcome. We discuss our findings in order to provide guidance for data acquisition. Our data is publicly available and might be used to further develop processing routines.


Assuntos
Microscopia Crioeletrônica/métodos , Tomografia com Microscopia Eletrônica/métodos , Benchmarking , Microscopia Crioeletrônica/normas , Bases de Dados Factuais , Tomografia com Microscopia Eletrônica/normas , HIV-1/química , HIV-1/ultraestrutura , Substâncias Macromoleculares/química , Substâncias Macromoleculares/ultraestrutura , Modelos Moleculares , Biologia Molecular/métodos , Biologia Molecular/normas , Vírion/química , Vírion/ultraestrutura
6.
Chem Commun (Camb) ; 56(20): 3015-3018, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32048648

RESUMO

The uncapped tripeptide DPhe-Phe-Leu acts as self-assembly template to yield supramolecular hydrogel biomaterials. As an example, self-assembling DPhe-Phe-Leu-Asp-Val contains the LDV bioadhesive motif for ß1 integrin activation. Hydrogels made of the two peptides successfully mimic fibronectin of the extracellular matrix and lead to high cell viability, adhesion, and spreading.


Assuntos
Hidrogéis/química , Imagem Óptica , Peptídeos/química , Adesão Celular , Sobrevivência Celular , Fibroblastos/química , Humanos , Substâncias Macromoleculares/química , Conformação Molecular , Tamanho da Partícula , Propriedades de Superfície
7.
Nucleic Acids Res ; 48(6): 3366-3378, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32052019

RESUMO

RNAs play major roles in the regulation of gene expression. Hence, designer RNA molecules are increasingly explored as regulatory switches in synthetic biology. Among these, the TetR-binding RNA aptamer was selected by its ability to compete with operator DNA for binding to the bacterial repressor TetR. A fortuitous finding was that induction of TetR by tetracycline abolishes both RNA aptamer and operator DNA binding in TetR. This enabled numerous applications exploiting both the specificity of the RNA aptamer and the efficient gene repressor properties of TetR. Here, we present the crystal structure of the TetR-RNA aptamer complex at 2.7 Å resolution together with a comprehensive characterization of the TetR-RNA aptamer versus TetR-operator DNA interaction using site-directed mutagenesis, size exclusion chromatography, electrophoretic mobility shift assays and isothermal titration calorimetry. The fold of the RNA aptamer bears no resemblance to regular B-DNA, and neither does the thermodynamic characterization of the complex formation reaction. Nevertheless, the functional aptamer-binding epitope of TetR is fully contained within its DNA-binding epitope. In the RNA aptamer complex, TetR adopts the well-characterized DNA-binding-competent conformation of TetR, thus revealing how the synthetic TetR-binding aptamer strikes the chords of the bimodal allosteric behaviour of TetR to function as a synthetic regulator.


Assuntos
Aptâmeros de Nucleotídeos/química , Proteínas de Ligação a DNA/ultraestrutura , Proteínas de Escherichia coli/ultraestrutura , Conformação Proteica , Aptâmeros de Nucleotídeos/genética , Cristalografia por Raios X , DNA de Forma B/química , DNA de Forma B/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Escherichia coli/genética , Escherichia coli/ultraestrutura , Proteínas de Escherichia coli/química , Regulação da Expressão Gênica/genética , Substâncias Macromoleculares/química , Substâncias Macromoleculares/ultraestrutura , Modelos Moleculares , Ligação Proteica/genética , RNA/química , RNA/genética
8.
Genes Dev ; 34(5-6): 398-412, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001511

RESUMO

Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hot spots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hot spots and provide access for the DNA double-strand break (DSB) machinery. Recombination hot spots are decorated by a unique combination of histone modifications not found at other regulatory elements. HELLS is recruited to hot spots by PRDM9 and is necessary for both histone modifications and DNA accessibility at hot spots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hot spot activation in which HELLS and PRDM9 form a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.


Assuntos
DNA Helicases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Recombinação Homóloga/genética , Meiose/fisiologia , Animais , Morte Celular/genética , Quebras de DNA de Cadeia Dupla , Células Germinativas/patologia , Código das Histonas/genética , Infertilidade Masculina/genética , Infertilidade Masculina/fisiopatologia , Substâncias Macromoleculares/metabolismo , Masculino , Meiose/genética , Camundongos
9.
Acta Crystallogr D Struct Biol ; 76(Pt 2): 155-165, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32038046

RESUMO

Reducing the sample-exchange time is a crucial issue in maximizing the throughput of macromolecular crystallography (MX) beamlines because the diffraction data collection itself is completed within a minute in the era of pixel-array detectors. To this end, an upgraded sample changer, SPACE-II, has been developed on the basis of the previous model, SPACE (SPring-8 Precise Automatic Cryo-sample Exchanger), at the BL41XU beamline at SPring-8. SPACE-II achieves one sample-exchange step within 16 s, of which its action accounts for only 11 s, because of three features: (i) the implementation of twin arms that enable samples to be exchanged in one cycle of mount-arm action, (ii) the implementation of long-stroke mount arms that allow samples to be exchanged without withdrawal of the detector and (iii) the use of a fast-moving translation and rotation stage for the mount arms. By pre-holding the next sample prior to the sample-exchange sequence, the time was further decreased to 11 s in the case of automatic data collection, of which the action of SPACE-II accounted for 8 s. Moreover, the sample capacity was expanded from four to eight Uni-Pucks. The performance of SPACE-II has been demonstrated in over two years of operation at BL41XU; the average number of samples mounted on the diffractometer in one day was increased from 132 to 185, with an error rate of 0.089%, which counted incidents in which users could not continue with an experiment without recovery work by entering the experimental hutch. On the basis of these results, SPACE-II has been installed at three other MX beamlines at SPring-8 as of July 2019. The fast and highly reliable SPACE-II is now one of the most important pieces of infrastructure for the MX beamlines at SPring-8, providing users with the opportunity to fully make use of limited beamtime with brilliant X-rays.


Assuntos
Automação , Cristalografia por Raios X/instrumentação , Coleta de Dados/métodos , Substâncias Macromoleculares/química , Cristalografia por Raios X/métodos , Robótica , Fatores de Tempo
10.
Nat Methods ; 17(3): 328-334, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32042190

RESUMO

Cryogenic electron microscopy (cryo-EM) maps are now at the point where resolvability of individual atoms can be achieved. However, resolvability is not necessarily uniform throughout the map. We introduce a quantitative parameter to characterize the resolvability of individual atoms in cryo-EM maps, the map Q-score. Q-scores can be calculated for atoms in proteins, nucleic acids, water, ligands and other solvent atoms, using models fitted to or derived from cryo-EM maps. Q-scores can also be averaged to represent larger features such as entire residues and nucleotides. Averaged over entire models, Q-scores correlate very well with the estimated resolution of cryo-EM maps for both protein and RNA. Assuming the models they are calculated from are well fitted to the map, Q-scores can be used as a measure of resolvability in cryo-EM maps at various scales, from entire macromolecules down to individual atoms. Q-score analysis of multiple cryo-EM maps of the same proteins derived from different laboratories confirms the reproducibility of structural features from side chains down to water and ion atoms.


Assuntos
Apoferritinas/química , Microscopia Crioeletrônica , Algoritmos , Animais , Análise de Fourier , Humanos , Ligação de Hidrogênio , Ligantes , Substâncias Macromoleculares/química , Camundongos , Microscopia Eletrônica , Modelos Moleculares , Distribuição Normal , Estrutura Secundária de Proteína , RNA/química , Solventes/química
11.
Arch Biochem Biophys ; 683: 108304, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32097611

RESUMO

The extraordinary flexibility and structural heterogeneity of intrinsically disordered proteins (IDP) make them functionally versatile molecules. We have now begun to better understand their fundamental role in biology, however many aspects of their behaviour remain difficult to grasp experimentally. This is especially true for the intermolecular interactions which lead to the formation of transient or highly dynamic supramolecular self-assemblies, such as oligomers, aggregation intermediates and biomolecular condensates. Both the emerging functions and pathogenicity of these structures have stimulated great efforts to develop methodologies capable of providing useful insights. Significant progress in solution NMR spectroscopy has made this technique one of the most powerful to describe structural and dynamic features of IDPs within such assemblies at atomic resolution. Here, we review the most recent works that have illuminated key aspects of IDP assemblies and contributed significant advancements towards our understanding of the complex conformational landscape of prototypical disease-associated proteins. We also include a primer on some of the fundamental and innovative NMR methods being used in the discussed studies.


Assuntos
Proteínas Amiloidogênicas/química , Proteínas Intrinsicamente Desordenadas/química , Espectroscopia de Ressonância Magnética , Adsorção , Humanos , Proteína Huntingtina/química , Cinética , Substâncias Macromoleculares , Peptídeos/química , Ligação Proteica , Conformação Proteica , Proteínas tau/química
12.
Chem Commun (Camb) ; 56(14): 2143-2146, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-31970346

RESUMO

In Nature, numerous proteins have evolved to perform similar roles, such as mechanical energy dispersion in different tissues. These biological macromolecules obtain their function from their tertiary structure, but proteins with similar roles can be quite different from each other, making it hard to define what structural features could be mimicked in synthetic materials in order to improve their performance. Here, we introduce an important protein feature - disulphide loops - into synthetic polymers and study the role of the loop size on mechanical energy dispersion. By stressing these polymers in solution, we were able to show, experimentally, that the loop size, up to a certain level, has a significant effect on the chain mechanochemical fragmentation rate, indicating it is affecting the polymer unfolding in solution prior to mechanochemical scission of the polymer backbone. Importantly, this experimental study uses homopolymers, providing information on an individual parameter - loop size - which cannot be obtained from comparing different proteins. This research emphasises the use of tailor-designed polymer-peptide hybrids to study fundamental questions on protein tertiary structures.


Assuntos
Dissulfetos/química , Polímeros/síntese química , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Estrutura Molecular , Polímeros/química
13.
Nat Commun ; 11(1): 488, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980618

RESUMO

Metallic lithium anodes are highly promising for revolutionizing current rechargeable batteries because of their ultrahigh energy density. However, the application of lithium metal batteries is considerably impeded by lithium dendrite growth. Here, a biomacromolecule matrix obtained from the natural membrane of eggshell is introduced to control lithium growth and the mechanism is motivated by how living organisms regulate the orientation of inorganic crystals in biomineralization. Specifically, cryo-electron microscopy is utilized to probe the structure of lithium at the atomic level. The dendrites growing along the preferred < 111 > crystallographic orientation are greatly suppressed in the presence of the biomacromolecule. Furthermore, the naturally soluble chemical species in the biomacromolecules can participate in the formation of solid electrolyte interphase upon cycling, thus effectively homogenizing the lithium deposition. The lithium anodes employing bioinspired design exhibit enhanced cycling capability. This work sheds light on identifying substantial challenges in lithium anodes for developing advanced batteries.


Assuntos
Fontes de Energia Elétrica , Lítio , Animais , Biomineralização , Engenharia Química , Microscopia Crioeletrônica , Cristalização , Casca de Ovo/química , Técnicas Eletroquímicas , Eletrodos , Lítio/química , Substâncias Macromoleculares/química , Trifluoretanol/química
14.
Macromol Rapid Commun ; 41(4): e1900611, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31958194

RESUMO

Herein, it is reported for the first time that when mixed with choline chloride, itaconic acid (IA), normally a low-reactive vinyl monomer, undergoes initiator-free radical polymerization under normal daylight. Furthermore, the process results in the formation of abnormally high-molecular-weight poly(itaconic acid) derivatives with Mw greater than ≈800 000 g mol-1 . Detailed 1D/2D NMR studies indicate that the polymers have two types of ionizable moieties, that is, anionic carboxylic and cationic choline ester groups in an average molar ratio of 12:1. Potentiometric titration shows polyampholyte behavior of the polymers. Tentative mechanistic studies reveal that the daylight-induced polymerization is initiated by species generated via interactions of near UV light with IA. However, EPR findings show that choline also participates in secondary radical reactions. The obtained polyampholytes are useful bio-based materials for fast and straightforward fabrication of polymer-clay nanocomposite hydrogels with excellent mechanical properties.


Assuntos
Radicais Livres/química , Polímeros/síntese química , Succinatos/química , Colina/química , Luz , Substâncias Macromoleculares/química , Peso Molecular , Polimerização/efeitos da radiação , Polímeros/química , Raios Ultravioleta
15.
Chemistry ; 26(1): 198-205, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31643112

RESUMO

A 2D supramolecular organic framework (SOF) based on synthetic macrocycles has been constructed in water by a self-assembly strategy. Two new organic monomers of this SOF, possessing viologen and azobenzene functional groups, form a stimuli-responsive host-guest system upon cooperatively binding with cucurbit[8]uril rings. The reversible formation and dissociation of 2D SOF can be realized by the isomerization of azobenzene under ultraviolet and visible light. The light-responsive property of the SOF is highly reversible and stable for up to four cycles. Moreover, azoreductase produced by Escherichia coli can reduce the N=N double bond of azobenzene entities, resulting in fluorescence recovery of the system. As an excellent and effective fluorescent probe, the SOF can detect azoreductase activity for real-time monitoring of the growth process of Escherichia coli. The dual-stimuli responsive 2D SOF is envisioned to drive the development of responsive devices with complex functions.


Assuntos
Substâncias Macromoleculares/química , NADH NADPH Oxirredutases/metabolismo , Compostos Azo/química , Hidrocarbonetos Aromáticos com Pontes/química , Escherichia coli/metabolismo , Imidazóis/química , Isomerismo , Luz , Substâncias Macromoleculares/metabolismo , NADH NADPH Oxirredutases/química , NADH NADPH Oxirredutases/genética , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Espectrometria de Fluorescência
16.
Chem Commun (Camb) ; 56(4): 539-542, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31829317

RESUMO

The first example of supramolecular recognition of phosphocholine by a cavitand receptor has been reported here. The chemical structure of the receptor has been optimized by DFT calculations. The recognition mechanism is based on a "multi-topic approach", which leads to highly efficient (K value up to 107 M-1), selective and sensitive (ppb level) sensing of phosphocholine. The recognition mechanism proposed here is similar to those exploited by Nature, and paves the way for the realization of new sensors with important applications in medicine and security fields.


Assuntos
Complexos de Coordenação/química , Fosforilcolina/análise , Zinco/química , Complexos de Coordenação/síntese química , Teoria da Densidade Funcional , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Estrutura Molecular
17.
J Chromatogr A ; 1609: 460491, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31481295

RESUMO

The development of multifarious stationary phases is still a growing demand so as to solve the tasks of ever evolving actual applications. Herein, with D-2-allylglycine hydrochloride (AG·HCl) as the hydrophilic monomer, diene ionic liquid 1-allyl-3-vinylimidazolium bromide (AVI·Br) and polyhedral oligomeric silsesquioxane methacryl substituted (POSS-MA) as the dual crosslinkers, the highly cross-linked imidazolium-bridged POSS-AVI-AG hybrid monolithic column was fabricated via the "one-pot" free radical copolymerization. The AG·HCl embedded POSS-AVI-AG column displays typical reversed-phase liquid chromatography/hydrophilic interaction liquid chromatography mixed-mode retention mechanisms. Both hydrophobic phenols, alkylbenzenes, aromatic amines and hydrophilic nucleosides/nucleic acid bases, amides and thioureas were successfully separated with high column efficiencies (up to 571,000 plates/m for amides), outperforming our previously reported AVI·Br modified POSS-AVI column. Moreover, the column was also explored for the separation of cytochrome c tryptic digests and egg white protein extraction. All these results demonstrate that the POSS-AVI-AG column has a good potential in separation of both small molecules and complex biological samples with multiple mechanisms.


Assuntos
Alilglicina/química , Imidazóis/química , Substâncias Macromoleculares/isolamento & purificação , Compostos de Organossilício/química , Citocromos c/isolamento & purificação , Nucleosídeos/isolamento & purificação , Peptídeos/isolamento & purificação , Polimerização , Proteínas/isolamento & purificação
18.
Eur J Med Chem ; 186: 111876, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761384

RESUMO

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) is a negative immune checkpoint pathway that inhibit immune responses, and upregulation of this pathway has implications in many malignancies. The search for effective PD-1/PD-L1 inhibitors has been at the forefront of academic and industrial medicinal chemistry, leading to 16 clinical candidates and the launch of six monoclonal antibodies (mAbs) drugs. Despite the unprecedented success achieved, the limitations of mAbs, including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, impelled researchers to turn their attention to the development of peptide-based and non-peptide small-molecule inhibitors as potential alternatives or supplements to mAbs. However, no small-molecule inhibitors have been approved so far, indicating a challenging process of developing marketable small-molecule PD-1/PD-L1 targeted therapeutics. This review will summarize and provide insight into recent advances in the PD-1/PD-L1 pathway, including its structural basis and biology, along with the crystal structures with mAbs, peptides and small molecules. We place great emphasis on design strategies underlying reported small-molecule inhibitors and attempt to provide an outlook at the future of small-molecule PD-1/PD-L1inhibitors.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Peptídeos/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Antígeno B7-H1/metabolismo , Relação Dose-Resposta a Droga , Humanos , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Estrutura Molecular , Peptídeos/química , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
19.
J Agric Food Chem ; 68(2): 451-460, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31834791

RESUMO

Atmospheric low-temperature plasma has emerged as a promising pretreatment for lignocellulose to improve bio-refining. Herein, we investigated plasma-induced changes in the chemical structure of lignin to obtain a fundamental understanding of the plasma-lignocellulose interaction. Based on the results, plasma possesses a strong capacity to cleave C-C covalent bonds in the aliphatic region of lignin, accompanied by oxidation. Plasma treatment leads to the degradation and fragmentation of lignin. Pronounced deconstruction of ß-O-4 aryl ether is observed in plasma. The relative content of ß-O-4 aryl ether was reduced from the initial value of 65.1/100Ar to 58.7/100Ar for lignin from corncob and from the initial value of 72.5/100Ar to 63.8/100Ar for lignin from poplar after plasma treatment, respectively. According to the density functional theory analysis, the oxygen atom of ß-O-4 aryl ether is the most likely potential reaction site and the Cß-O covalent bond exhibits the lowest decomposition free energy (50.5 kcal mol-1), which will easily be cleaved in plasma. The dominant reaction pathway of lignin degradation is the cleavage of the Cß-O covalent bond followed by the cleavage of the Cß-Cα bond. We propose that this investigation is beneficial to optimize and expand the applications of plasma treatment in pretreatment of lignocellulose.


Assuntos
Lignina/química , Substâncias Macromoleculares/química , Gases em Plasma/química , Temperatura Baixa , Modelos Moleculares , Oxirredução , Oxigênio/química
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