Structure of the CoA transferase from pig heart to 1.7 Å resolution

Coros, Abbie M.; Swenson, Lora; Wolodko, William T.; Fraser, M.E.

doi:10.1107/s0907444904017974

Cited by 16 publications

(17 citation statements)

References 31 publications

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“…This requirement likely forces the acyl backbone into the adjacent N-terminal pocket formed by Phe85, Phe60, Phe113, Met31 and Glu61 ( Figures 6B and 7 ). With the exception of Glu61, which is protonated and polar, the pocket is entirely apolar, resembling those described in C. aminobutyricum 4-HBCoAT [14] and SCOT [25], [26] with Phe85, Phe60 and Phe113 conserved in all 4-HBCoATs. The pocket size, which restricts the size of the acyl group that can bind effectively, appears to be large enough to accommodate acyl groups of three to four carbon atoms and helps explain the competition and DSF assays.…”

Section: Discussionmentioning

confidence: 55%

Biochemical, Structural and Molecular Dynamics Analyses of the Potential Virulence Factor RipA from Yersinia pestis

et al. 2011

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Human diseases are attributed in part to the ability of pathogens to evade the eukaryotic immune systems. A subset of these pathogens has developed mechanisms to survive in human macrophages. Yersinia pestis, the causative agent of the bubonic plague, is a predominately extracellular pathogen with the ability to survive and replicate intracellularly. A previous study has shown that a novel rip (required for intracellular proliferation) operon (ripA, ripB and ripC) is essential for replication and survival of Y. pestis in postactivated macrophages, by playing a role in lowering macrophage-produced nitric oxide (NO) levels. A bioinformatics analysis indicates that the rip operon is conserved among a distally related subset of macrophage-residing pathogens, including Burkholderia and Salmonella species, and suggests that this previously uncharacterized pathway is also required for intracellular survival of these pathogens. The focus of this study is ripA, which encodes for a protein highly homologous to 4-hydroxybutyrate-CoA transferase; however, biochemical analysis suggests that RipA functions as a butyryl-CoA transferase. The 1.9 Å X-ray crystal structure reveals that RipA belongs to the class of Family I CoA transferases and exhibits a unique tetrameric state. Molecular dynamics simulations are consistent with RipA tetramer formation and suggest a possible gating mechanism for CoA binding mediated by Val227. Together, our structural characterization and molecular dynamic simulations offer insights into acyl-CoA specificity within the active site binding pocket, and support biochemical results that RipA is a butyryl-CoA transferase. We hypothesize that the end product of the rip operon is butyrate, a known anti-inflammatory, which has been shown to lower NO levels in macrophages. Thus, the results of this molecular study of Y. pestis RipA provide a structural platform for rational inhibitor design, which may lead to a greater understanding of the role of RipA in this unique virulence pathway.

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Section: Discussionmentioning

confidence: 55%

Biochemical, Structural and Molecular Dynamics Analyses of the Potential Virulence Factor RipA from Yersinia pestis

et al. 2011

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“…It directly interacts with the acyl CoA (E54 in glutaconate CoA transferase, 1poi and E305 in SCOT, 1m3e and 1ope) and participates in the transfer reaction by forming a thioester bond with CoA. 21,23,47 Its absence in CitF and MdcA is consistent with the fact that they use acyl-S-acyl carrier protein (ACP) substrates rather than acylCoAs. In the catalytically inactive domains of the CoA transferase assemblage (see below) the corresponding region has lost the polar residues and instead contains a patch of small residues that line the substrate-binding pocket and are likely to interact with it (Figures 1 and 4).…”

Section: Common Active Site Features Of the Isocot Foldmentioning

confidence: 79%

“…The two subunits are functionally distinct with only one of them playing a central role in catalysis (see below). 21,23,47 Members of this assemblage may also show certain distinct conserved sequence features in the hairpin formed by S4a and S4b (Figure 1). …”

Section: The Coa Transferase Assemblagementioning

confidence: 99%

Diversification of Catalytic Activities and Ligand Interactions in the Protein Fold Shared by the Sugar Isomerases, eIF2B, DeoR Transcription Factors, Acyl-CoA Transferases and Methenyltetrahydrofolate Synthetase

Anantharaman

Aravind

2006

Journal of Molecular Biology

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“…1OOY also functions as a succinyl-CoA:3-ketoacid CoA transferase. Even though the template lacks a bound ligand, biochemical studies show that N281, Q99, G386, and A387 are conserved in CoAtransferases, and correspondingly, these residues were also conserved in the model of Rv2503c (62). Furthermore, binding site residues predicted by both PocketDepth (56) and SURFnet (63) show that these residues lie within the predicted binding pocket of Rv2503c (Fig.…”

Section: Enrichment Of Functional Annotationmentioning

confidence: 92%

Structural Annotation of the Mycobacterium tuberculosis Proteome

Chandra

Sandhya

2014

Microbiol Spectr

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Efforts from the TB Structural Genomics Consortium together with those of tuberculosis structural biologists worldwide have led to the determination of about 350 structures, making up nearly a tenth of the pathogen's proteome. Given that knowledge of protein structures is essential to obtaining a high-resolution understanding of the underlying biology, it is desirable to have a structural view of the entire proteome. Indeed, structure prediction methods have advanced sufficiently to allow structural models of many more proteins to be built based on homology modeling and fold recognition strategies. By means of these approaches, structural models for about 2,877 proteins, making up nearly 70% of the Mycobacterium tuberculosis proteome, are available. Knowledge from bioinformatics has made significant inroads into an improved annotation of the M. tuberculosis genome and in the prediction of key protein players that interact in vital pathways, some of which are unique to the organism. Functional inferences have been made for a large number of proteins based on fold-function associations. More importantly, ligand-binding pockets of the proteins are identified and scanned against a large database, leading to binding site–based ligand associations and hence structure-based function annotation. Near proteome-wide structural models provide a global perspective of the fold distribution in the genome. New insights about the folds that predominate in the genome, as well as the fold combinations that make up multidomain proteins, are also obtained. This chapter describes the structural proteome, functional inferences drawn from it, and its applications in drug discovery.

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Structure of the CoA transferase from pig heart to 1.7 Å resolution

Cited by 16 publications

References 31 publications

Biochemical, Structural and Molecular Dynamics Analyses of the Potential Virulence Factor RipA from Yersinia pestis

Biochemical, Structural and Molecular Dynamics Analyses of the Potential Virulence Factor RipA from Yersinia pestis

Diversification of Catalytic Activities and Ligand Interactions in the Protein Fold Shared by the Sugar Isomerases, eIF2B, DeoR Transcription Factors, Acyl-CoA Transferases and Methenyltetrahydrofolate Synthetase

Structural Annotation of the Mycobacterium tuberculosis Proteome

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