Document Detail

The binding mechanism, multiple binding modes, and allosteric regulation of Staphylococcus aureus Sortase A probed by molecular dynamics simulations.
MedLine Citation:
PMID:  23023444     Owner:  NLM     Status:  MEDLINE    
Sortase enzymes are vitally important for the virulence of gram-positive bacteria as they play a key role in the attachment of surface proteins to the cell wall. These enzymes recognize a specific sorting sequence in proteins destined to be displayed on the surface of the bacteria and catalyze the transpeptidation reaction that links it to a cell wall precursor molecule. Because of their role in establishing pathogenicity, and in light of the recent rise of antibiotic-resistant bacterial strains, sortase enzymes are novel drug targets. Here, we present a study of the prototypical sortase protein Staphylococcus aureus Sortase A (SrtA). Both conventional and accelerated molecular dynamics simulations of S. aureus SrtA in its apo state and when bound to an LPATG sorting signal (SS) were performed. Results support a binding mechanism that may be characterized as conformational selection followed by induced fit. Additionally, the SS was found to adopt multiple metastable states, thus resolving discrepancies between binding conformations in previously reported experimental structures. Finally, correlation analysis reveals that the SS actively affects allosteric pathways throughout the protein that connect the first and the second substrate binding sites, which are proposed to be located on opposing faces of the protein. Overall, these calculations shed new light on the role of dynamics in the binding mechanism and function of sortase enzymes.
Kalli Kappel; Jeff Wereszczynski; Robert T Clubb; J Andrew McCammon
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Protein science : a publication of the Protein Society     Volume:  21     ISSN:  1469-896X     ISO Abbreviation:  Protein Sci.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-27     Completed Date:  2013-04-29     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  9211750     Medline TA:  Protein Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1858-71     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 The Protein Society.
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MeSH Terms
Allosteric Regulation
Aminoacyltransferases / chemistry,  metabolism*
Bacterial Proteins / chemistry,  metabolism*
Cysteine Endopeptidases / chemistry,  metabolism*
Molecular Dynamics Simulation*
Protein Binding
Protein Conformation
Protein Sorting Signals
Staphylococcus aureus / chemistry,  enzymology*
Grant Support
AI52217/AI/NIAID NIH HHS; F32GM093581/GM/NIGMS NIH HHS; R01 AI052217/AI/NIAID NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Bacterial Proteins; 0/Protein Sorting Signals; EC 2.3.2.-/Aminoacyltransferases; EC 2.3.2.-/sortase A; EC 3.4.22.-/Cysteine Endopeptidases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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