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1.
Bioorg Med Chem Lett ; 96: 129492, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37778428

RESUMEN

Natural killer group 2D (NKG2D) is a homodimeric activating immunoreceptor whose function is to detect and eliminate compromised cells upon binding to the NKG2D ligands (NKG2DL) major histocompatibility complex (MHC) molecules class I-related chain A (MICA) and B (MICB) and UL16 binding proteins (ULBP1-6). While typically present at low levels in healthy cells and tissue, NKG2DL expression can be induced by viral infection, cellular stress or transformation. Aberrant activity along the NKG2D/NKG2DL axis has been associated with autoimmune diseases due to the increased expression of NKG2D ligands in human disease tissue, making NKG2D inhibitors an attractive target for immunomodulation. Herein we describe the discovery and optimization of small molecule PPI (protein-protein interaction) inhibitors of NKG2D/NKG2DL. Rapid SAR was guided by structure-based drug design and accomplished by iterative singleton and parallel medicinal chemistry synthesis. These efforts resulted in the identification of several potent analogs (14, 21, 30, 45) with functional activity and improved LLE.


Asunto(s)
Proteínas Portadoras , Subfamilia K de Receptores Similares a Lectina de Células NK , Humanos , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Proteínas Portadoras/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Unión Proteica , Células Asesinas Naturales/metabolismo , Ligandos
2.
Proc Natl Acad Sci U S A ; 120(18): e2216342120, 2023 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-37098070

RESUMEN

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ+, and CD8+ T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.


Asunto(s)
Células Asesinas Naturales , Subfamilia K de Receptores Similares a Lectina de Células NK , Ligandos , Linfocitos T CD8-positivos , Unión Proteica
3.
Protein Sci ; 28(9): 1676-1689, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31306512

RESUMEN

Free-standing single-layer ß-sheets are extremely rare in naturally occurring proteins, even though ß-sheet motifs are ubiquitous. Here we report the crystal structures of three homologous, single-layer, anti-parallel ß-sheet proteins, comprised of three or four twisted ß-hairpin repeats. The structures reveal that, in addition to the hydrogen bond network characteristic of ß-sheets, additional hydrophobic interactions mediated by small clusters of residues adjacent to the turns likely play a significant role in the structural stability and compensate for the lack of a compact hydrophobic core. These structures enabled identification of a family of secreted proteins that are broadly distributed in bacteria from the human gut microbiome and are putatively involved in the metabolism of complex carbohydrates. A conserved surface patch, rich in solvent-exposed tyrosine residues, was identified on the concave surface of the ß-sheet. These new modular single-layer ß-sheet proteins may serve as a new model system for studying folding and design of ß-rich proteins.


Asunto(s)
Bacterias/metabolismo , Proteínas Bacterianas/química , Bacterias/química , Cristalografía por Rayos X , Microbioma Gastrointestinal , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformación Proteica en Lámina beta , Pliegue de Proteína , Tirosina/química
4.
Cell ; 165(3): 690-703, 2016 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-27062925

RESUMEN

Pili are proteinaceous polymers of linked pilins that protrude from the cell surface of many bacteria and often mediate adherence and virulence. We investigated a set of 20 Bacteroidia pilins from the human microbiome whose structures and mechanism of assembly were unknown. Crystal structures and biochemical data revealed a diverse protein superfamily with a common Greek-key ß sandwich fold with two transthyretin-like repeats that polymerize into a pilus through a strand-exchange mechanism. The assembly mechanism of the central, structural pilins involves proteinase-assisted removal of their N-terminal ß strand, creating an extended hydrophobic groove that binds the C-terminal donor strands of the incoming pilin. Accessory pilins at the tip and base have unique structural features specific to their location, allowing initiation or termination of the assembly. The Bacteroidia pilus, therefore, has a biogenesis mechanism that is distinct from other known pili and likely represents a different type of bacterial pilus.


Asunto(s)
Proteínas Fimbrias/química , Fimbrias Bacterianas , Microbioma Gastrointestinal , Secuencia de Aminoácidos , Cristalografía por Rayos X , Proteínas Fimbrias/genética , Proteínas Fimbrias/metabolismo , Humanos , Lipoproteínas/química , Lipoproteínas/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Alineación de Secuencia
5.
mBio ; 6(5): e02327-14, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26374125

RESUMEN

UNLABELLED: Bacterial SH3 (SH3b) domains are commonly fused with papain-like Nlp/P60 cell wall hydrolase domains. To understand how the modular architecture of SH3b and NlpC/P60 affects the activity of the catalytic domain, three putative NlpC/P60 cell wall hydrolases were biochemically and structurally characterized. These enzymes all have γ-d-Glu-A2pm (A2pm is diaminopimelic acid) cysteine amidase (or dl-endopeptidase) activities but with different substrate specificities. One enzyme is a cell wall lysin that cleaves peptidoglycan (PG), while the other two are cell wall recycling enzymes that only cleave stem peptides with an N-terminal l-Ala. Their crystal structures revealed a highly conserved structure consisting of two SH3b domains and a C-terminal NlpC/P60 catalytic domain, despite very low sequence identity. Interestingly, loops from the first SH3b domain dock into the ends of the active site groove of the catalytic domain, remodel the substrate binding site, and modulate substrate specificity. Two amino acid differences at the domain interface alter the substrate binding specificity in favor of stem peptides in recycling enzymes, whereas the SH3b domain may extend the peptidoglycan binding surface in the cell wall lysins. Remarkably, the cell wall lysin can be converted into a recycling enzyme with a single mutation. IMPORTANCE: Peptidoglycan is a meshlike polymer that envelops the bacterial plasma membrane and bestows structural integrity. Cell wall lysins and recycling enzymes are part of a set of lytic enzymes that target covalent bonds connecting the amino acid and amino sugar building blocks of the PG network. These hydrolases are involved in processes such as cell growth and division, autolysis, invasion, and PG turnover and recycling. To avoid cleavage of unintended substrates, these enzymes have very selective substrate specificities. Our biochemical and structural analysis of three modular NlpC/P60 hydrolases, one lysin, and two recycling enzymes, show that they may have evolved from a common molecular architecture, where the substrate preference is modulated by local changes. These results also suggest that new pathways for recycling PG turnover products, such as tracheal cytotoxin, may have evolved in bacteria in the human gut microbiome that involve NlpC/P60 cell wall hydrolases.


Asunto(s)
Aminopeptidasas/química , Aminopeptidasas/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Dominios Homologos src , Aminopeptidasas/genética , Proteínas Bacterianas/genética , Dominio Catalítico , Cristalografía por Rayos X , Análisis Mutacional de ADN , Modelos Moleculares , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Conformación Proteica , Especificidad por Sustrato
6.
Structure ; 22(12): 1799-1809, 2014 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-25465128

RESUMEN

GlcNAc-1,6-anhydro-MurNAc-tetrapeptide is a major peptidoglycan degradation intermediate and a cytotoxin. It is generated by lytic transglycosylases and further degraded and recycled by various enzymes. We have identified and characterized a highly specific N-acetylmuramoyl-L-alanine amidase (AmiA) from Bacteroides uniformis, a member of the DUF1460 protein family, that hydrolyzes GlcNAc-1,6-anhydro-MurNAc-peptide into disaccharide and stem peptide. The high-resolution apo structure at 1.15 Šresolution shows that AmiA is related to NlpC/P60 γ-D-Glu-meso-diaminopimelic acid amidases and shares a common catalytic core and cysteine peptidase-like active site. AmiA has evolved structural adaptations that reconfigure the substrate recognition site. The preferred substrates for AmiA were predicted in silico based on structural and bioinformatics data, and subsequently were characterized experimentally. Further crystal structures of AmiA in complexes with GlcNAc-1,6-anhydro-MurNAc and GlcNAc have enabled us to elucidate substrate recognition and specificity. DUF1460 is highly conserved in structure and defines another amidase family.


Asunto(s)
Modelos Moleculares , N-Acetil Muramoil-L-Alanina Amidasa/metabolismo , Peptidoglicano/metabolismo , Bacteroides , Cristalografía por Rayos X , Conformación Proteica , Relación Estructura-Actividad , Especificidad por Sustrato
7.
Acta Crystallogr D Biol Crystallogr ; 70(Pt 10): 2640-51, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25286848

RESUMEN

The crystal structure of arabinose-5-phosphate isomerase (API) from Bacteroides fragilis (bfAPI) was determined at 1.7 Šresolution and was found to be a tetramer of a single-domain sugar isomerase (SIS) with an endogenous ligand, CMP-Kdo (cytidine 5'-monophosphate-3-deoxy-D-manno-oct-2-ulosonate), bound at the active site. API catalyzes the reversible isomerization of D-ribulose 5-phosphate to D-arabinose 5-phosphate in the first step of the Kdo biosynthetic pathway. Interestingly, the bound CMP-Kdo is neither the substrate nor the product of the reaction catalyzed by API, but corresponds to the end product in the Kdo biosynthetic pathway and presumably acts as a feedback inhibitor for bfAPI. The active site of each monomer is located in a surface cleft at the tetramer interface between three monomers and consists of His79 and His186 from two different adjacent monomers and a Ser/Thr-rich region, all of which are highly conserved across APIs. Structure and sequence analyses indicate that His79 and His186 may play important catalytic roles in the isomerization reaction. CMP-Kdo mimetics could therefore serve as potent and specific inhibitors of API and provide broad protection against many different bacterial infections.


Asunto(s)
Isomerasas Aldosa-Cetosa/química , Isomerasas Aldosa-Cetosa/metabolismo , Bacteroides fragilis/química , Isomerasas Aldosa-Cetosa/genética , Secuencia de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Dominio Catalítico , Cristalografía por Rayos X , Citidina Monofosfato/análogos & derivados , Citidina Monofosfato/química , Histidina/química , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Homología de Secuencia de Aminoácido , Azúcares Ácidos/química
8.
PLoS One ; 9(9): e107309, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25197798

RESUMEN

Kanadaptin is a nuclear protein of unknown function that is widely expressed in mammalian tissues. The crystal structure of the forkhead-associated (FHA) domain of human kanadaptin was determined to 1.6 Å resolution. The structure reveals an asymmetric dimer in which one monomer is complexed with a phosphopeptide mimic derived from a peptide segment from the N-terminus of a symmetry-related molecule as well as a sulfate bound to the structurally conserved phosphothreonine recognition cleft. This structure provides insights into the molecular recognition features utilized by this family of proteins and represents the first evidence that kanadaptin is likely involved in a phosphorylation-mediated signaling pathway. These results will be of use for designing experiments to further probe the function of kanadaptin.


Asunto(s)
Antiportadores/química , Antiportadores/metabolismo , Fosfopéptidos/metabolismo , Secuencia de Aminoácidos , Animales , Sitios de Unión , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Fosfopéptidos/química , Unión Proteica , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína
9.
Protein Sci ; 23(10): 1380-91, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25044324

RESUMEN

Crystal structures of three members (BACOVA_00364 from Bacteroides ovatus, BACUNI_03039 from Bacteroides uniformis and BACEGG_00036 from Bacteroides eggerthii) of the Pfam domain of unknown function (DUF4488) were determined to 1.95, 1.66, and 1.81 Å resolutions, respectively. The protein structures adopt an eight-stranded, calycin-like, ß-barrel fold and bind an endogenous unknown ligand at one end of the ß-barrel. The amino acids interacting with the ligand are not conserved in any other protein of known structure with this particular fold. The size and chemical environment of the bound ligand suggest binding or transport of a small polar molecule(s) as a potential function for these proteins. These are the first structural representatives of a newly defined PF14869 (DUF4488) Pfam family.


Asunto(s)
Proteínas Bacterianas/química , Bacteroides/metabolismo , Metabolismo de los Hidratos de Carbono , Bacteroides/química , Sitios de Unión , Cristalografía por Rayos X , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Secundaria de Proteína , Alineación de Secuencia
10.
Proteins ; 82(6): 1086-92, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24174223

RESUMEN

Pseudomonas aeruginosa is an opportunistic pathogen commonly found in humans and other organisms and is an important cause of infection especially in patients with compromised immune defense mechanisms. The PA3611 gene of P. aeruginosa PAO1 encodes a secreted protein of unknown function, which has been recently classified into a small Pseudomonas-specific protein family called DUF4146. As part of our effort to extend structural coverage of novel protein space and provide a structure-based functional insight into new protein families, we report the crystal structure of PA3611, the first structural representative of the DUF4146 protein family.


Asunto(s)
Proteínas Bacterianas/química , Pseudomonas aeruginosa , Secuencia de Aminoácidos , Secuencia Conservada , Cristalografía por Rayos X , Modelos Moleculares , Estructura Secundaria de Proteína , Percepción de Quorum
11.
J Bacteriol ; 195(24): 5555-66, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24123814

RESUMEN

Approximately 50% of cell wall peptidoglycan in Gram-negative bacteria is recycled with each generation. The primary substrates used for peptidoglycan biosynthesis and recycling in the cytoplasm are GlcNAc-MurNAc(anhydro)-tetrapeptide and its degradation product, the free tetrapeptide. This complex process involves ∼15 proteins, among which the cytoplasmic enzyme ld-carboxypeptidase A (LdcA) catabolizes the bond between the last two l- and d-amino acid residues in the tetrapeptide to form the tripeptide, which is then utilized as a substrate by murein peptide ligase (Mpl). LdcA has been proposed as an antibacterial target. The crystal structure of Novosphingobium aromaticivorans DSM 12444 LdcA (NaLdcA) was determined at 1.89-Šresolution. The enzyme was biochemically characterized and its interactions with the substrate modeled, identifying residues potentially involved in substrate binding. Unaccounted electron density at the dimer interface in the crystal suggested a potential site for disrupting protein-protein interactions should a dimer be required to perform its function in bacteria. Our analysis extends the identification of functional residues to several other homologs, which include enzymes from bacteria that are involved in hydrocarbon degradation and destruction of coral reefs. The NaLdcA crystal structure provides an alternate system for investigating the structure-function relationships of LdcA and increases the structural coverage of the protagonists in bacterial cell wall recycling.


Asunto(s)
Carboxipeptidasas/química , Carboxipeptidasas/metabolismo , Peptidoglicano/metabolismo , Sphingomonadaceae/enzimología , Secuencia de Aminoácidos , Sitios de Unión , Cristalografía por Rayos X , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Conformación Proteica , Multimerización de Proteína
12.
J Biol Chem ; 288(23): 16789-16799, 2013 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-23572527

RESUMEN

DUF2233, a domain of unknown function (DUF), is present in many bacterial and several viral proteins and was also identified in the mammalian transmembrane glycoprotein N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase ("uncovering enzyme" (UCE)). We report the crystal structure of BACOVA_00430, a 315-residue protein from the human gut bacterium Bacteroides ovatus that is the first structural representative of the DUF2233 protein family. A notable feature of this structure is the presence of a surface cavity that is populated by residues that are highly conserved across the entire family. The crystal structure was used to model the luminal portion of human UCE (hUCE), which is involved in targeting of lysosomal enzymes. Mutational analysis of several residues in a highly conserved surface cavity of hUCE revealed that they are essential for function. The bacterial enzyme (BACOVA_00430) has ∼1% of the catalytic activity of hUCE toward the substrate GlcNAc-P-mannose, the precursor of the Man-6-P lysosomal targeting signal. GlcNAc-1-P is a poor substrate for both enzymes. We conclude that, for at least a subset of proteins in this family, DUF2233 functions as a phosphodiester glycosidase.


Asunto(s)
Proteínas Bacterianas/química , Bacteroides/enzimología , Hidrolasas Diéster Fosfóricas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Dominio Catalítico , Cristalografía por Rayos X , Humanos , Mutagénesis , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Homología Estructural de Proteína
13.
PLoS One ; 6(7): e21875, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21799754

RESUMEN

Imelysin-like proteins define a superfamily of bacterial proteins that are likely involved in iron uptake. Members of this superfamily were previously thought to be peptidases and were included in the MEROPS family M75. We determined the first crystal structures of two remotely related, imelysin-like proteins. The Psychrobacter arcticus structure was determined at 2.15 Å resolution and contains the canonical imelysin fold, while higher resolution structures from the gut bacteria Bacteroides ovatus, in two crystal forms (at 1.25 Å and 1.44 Å resolution), have a circularly permuted topology. Both structures are highly similar to each other despite low sequence similarity and circular permutation. The all-helical structure can be divided into two similar four-helix bundle domains. The overall structure and the GxHxxE motif region differ from known HxxE metallopeptidases, suggesting that imelysin-like proteins are not peptidases. A putative functional site is located at the domain interface. We have now organized the known homologous proteins into a superfamily, which can be separated into four families. These families share a similar functional site, but each has family-specific structural and sequence features. These results indicate that imelysin-like proteins have evolved from a common ancestor, and likely have a conserved function.


Asunto(s)
Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Bacteroides/metabolismo , Hierro/metabolismo , Psychrobacter/metabolismo , Análisis de Secuencia de Proteína , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Transporte Biológico , Secuencia Conservada , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Relación Estructura-Actividad
14.
Acta Crystallogr Sect F Struct Biol Cryst Commun ; 66(Pt 10): 1153-9, 2010 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-20944205

RESUMEN

The first structural representative of the domain of unknown function DUF2006 family, also known as Pfam family PF09410, comprises a lipocalin-like fold with domain duplication. The finding of the calycin signature in the N-terminal domain, combined with remote sequence similarity to two other protein families (PF07143 and PF08622) implicated in isoprenoid metabolism and the oxidative stress response, support an involvement in lipid metabolism. Clusters of conserved residues that interact with ligand mimetics suggest that the binding and regulation sites map to the N-terminal domain and to the interdomain interface, respectively.


Asunto(s)
Proteínas Bacterianas/química , Bases de Datos Genéticas , Metabolismo de los Lípidos , Nitrosomonas europaea/química , Secuencia de Aminoácidos , Cristalografía por Rayos X , Modelos Moleculares , Datos de Secuencia Molecular , Nitrosomonas europaea/metabolismo , Estrés Oxidativo , Estructura Terciaria de Proteína , Alineación de Secuencia , Homología de Secuencia de Aminoácido
15.
Acta Crystallogr Sect F Struct Biol Cryst Commun ; 66(Pt 10): 1160-6, 2010 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-20944206

RESUMEN

SSO2064 is the first structural representative of PF01796 (DUF35), a large prokaryotic family with a wide phylogenetic distribution. The structure reveals a novel two-domain architecture comprising an N-terminal, rubredoxin-like, zinc ribbon and a C-terminal, oligonucleotide/oligosaccharide-binding (OB) fold domain. Additional N-terminal helical segments may be involved in protein-protein interactions. Domain architectures, genomic context analysis and functional evidence from certain bacterial representatives of this family suggest that these proteins form a novel fatty-acid-binding component that is involved in the biosynthesis of lipids and polyketide antibiotics and that they possibly function as acyl-CoA-binding proteins. This structure has led to a re-evaluation of the DUF35 family, which has now been split into two entries in the latest Pfam release (v.24.0).


Asunto(s)
Acilcoenzima A/química , Proteínas Arqueales/química , Pliegue de Proteína , Sulfolobus solfataricus/química , Zinc/química , Secuencia de Aminoácidos , Proteínas Arqueales/genética , Proteínas Arqueales/metabolismo , Cristalografía por Rayos X , Genoma Arqueal , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Estructura Terciaria de Proteína , Sulfolobus solfataricus/genética , Sulfolobus solfataricus/metabolismo
16.
Acta Crystallogr Sect F Struct Biol Cryst Commun ; 66(Pt 10): 1167-73, 2010 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-20944207

RESUMEN

The crystal structure of Dhaf4260 from Desulfitobacterium hafniense DCB-2 was determined by single-wavelength anomalous diffraction (SAD) to a resolution of 2.01 Šusing the semi-automated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). This protein structure is the first representative of the PF04016 (DUF364) Pfam family and reveals a novel combination of two well known domains (an enolase N-terminal-like fold followed by a Rossmann-like domain). Structural and bioinformatic analyses reveal partial similarities to Rossmann-like methyltransferases, with residues from the enolase-like fold combining to form a unique active site that is likely to be involved in the condensation or hydrolysis of molecules implicated in the synthesis of flavins, pterins or other siderophores. The genome context of Dhaf4260 and homologs additionally supports a role in heavy-metal chelation.


Asunto(s)
Proteínas Bacterianas/química , Desulfitobacterium/química , Metales Pesados/química , Fosfopiruvato Hidratasa/química , Pliegue de Proteína , Secuencia de Aminoácidos , Proteínas Bacterianas/metabolismo , Dominio Catalítico , Cristalografía por Rayos X , Desulfitobacterium/metabolismo , Metales Pesados/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Estructura Terciaria de Proteína
17.
Acta Crystallogr Sect F Struct Biol Cryst Commun ; 66(Pt 10): 1174-81, 2010 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-20944208

RESUMEN

Proteins with the DUF2063 domain constitute a new Pfam family, PF09836. The crystal structure of a member of this family, NGO1945 from Neisseria gonorrhoeae, has been determined and reveals that the N-terminal DUF2063 domain is likely to be a DNA-binding domain. In conjunction with the rest of the protein, NGO1945 is likely to be involved in transcriptional regulation, which is consistent with genomic neighborhood analysis. Of the 216 currently known proteins that contain a DUF2063 domain, the most significant sequence homologs of NGO1945 (∼40-99% sequence identity) are from various Neisseria and Haemophilus species. As these are important human pathogens, NGO1945 represents an interesting candidate for further exploration via biochemical studies and possible therapeutic intervention.


Asunto(s)
Proteínas Bacterianas/química , Regulación de la Expresión Génica , Neisseria gonorrhoeae/química , Transcripción Genética , Secuencia de Aminoácidos , Proteínas Bacterianas/genética , Cristalografía por Rayos X , Genoma Bacteriano , Modelos Moleculares , Datos de Secuencia Molecular , Neisseria gonorrhoeae/genética , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Homología Estructural de Proteína
18.
Acta Crystallogr Sect F Struct Biol Cryst Commun ; 66(Pt 10): 1182-9, 2010 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-20944209

RESUMEN

The crystal structures of BB2672 and SPO0826 were determined to resolutions of 1.7 and 2.1 Šby single-wavelength anomalous dispersion and multiple-wavelength anomalous dispersion, respectively, using the semi-automated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). These proteins are the first structural representatives of the PF06684 (DUF1185) Pfam family. Structural analysis revealed that both structures adopt a variant of the Bacillus chorismate mutase fold (BCM). The biological unit of both proteins is a hexamer and analysis of homologs indicates that the oligomer interface residues are highly conserved. The conformation of the critical regions for oligomerization appears to be dependent on pH or salt concentration, suggesting that this protein might be subject to environmental regulation. Structural similarities to BCM and genome-context analysis suggest a function in amino-acid synthesis.


Asunto(s)
Aminoácidos/metabolismo , Bordetella bronchiseptica/enzimología , Corismato Mutasa/química , Pliegue de Proteína , Rhodobacteraceae/enzimología , Secuencia de Aminoácidos , Bacillus/enzimología , Corismato Mutasa/metabolismo , Cristalografía por Rayos X , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Homología Estructural de Proteína
19.
Acta Crystallogr Sect F Struct Biol Cryst Commun ; 66(Pt 10): 1198-204, 2010 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-20944211

RESUMEN

The crystal structure of Jann_2411 from Jannaschia sp. strain CCS1, a member of the Pfam PF07336 family classified as a domain of unknown function (DUF1470), was solved to a resolution of 1.45 Šby multiple-wavelength anomalous dispersion (MAD). This protein is the first structural representative of the DUF1470 Pfam family. Structural analysis revealed a two-domain organization, with the N-terminal domain presenting a new fold called the ABATE domain that may bind an as yet unknown ligand. The C-terminal domain forms a treble-clef zinc finger that is likely to be involved in DNA binding. Analysis of the Jann_2411 protein and the broader ABATE-domain family suggests a role as stress-induced transcriptional regulators.


Asunto(s)
Proteínas Bacterianas/química , Rhodobacteraceae/química , Secuencia de Aminoácidos , Cristalografía por Rayos X , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Alineación de Secuencia , Dedos de Zinc
20.
Acta Crystallogr Sect F Struct Biol Cryst Commun ; 66(Pt 10): 1205-10, 2010 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-20944212

RESUMEN

The structure of LP2179, a member of the PF08866 (DUF1831) family, suggests a novel α+ß fold comprising two ß-sheets packed against a single helix. A remote structural similarity to two other uncharacterized protein families specific to the Bacillus genus (PF08868 and PF08968), as well as to prokaryotic S-adenosylmethionine decarboxylases, is consistent with a role in amino-acid metabolism. Genomic neighborhood analysis of LP2179 supports this functional assignment, which might also then be extended to PF08868 and PF08968.


Asunto(s)
Aminoácidos/metabolismo , Proteínas Bacterianas/química , Lactobacillus plantarum/química , Pliegue de Proteína , Secuencia de Aminoácidos , Proteínas Bacterianas/metabolismo , Cristalografía por Rayos X , Lactobacillus plantarum/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Alineación de Secuencia , Homología Estructural de Proteína
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