| Structure-based design of a periplasmic binding protein antagonist that prevents domain closure. | |
| | |
MedLine Citation:
|
PMID: 19348466 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Many receptors undergo ligand-induced conformational changes to initiate signal transduction. Periplasmic binding proteins (PBPs) are bacterial receptors that exhibit dramatic conformational changes upon ligand binding. These proteins mediate a wide variety of fundamental processes including transport, chemotaxis, and quorum sensing. Despite the importance of these receptors, no PBP antagonists have been identified and characterized. In this study, we identify 3-O-methyl-d-glucose as an antagonist of glucose/galactose-binding protein and demonstrate that it inhibits glucose chemotaxis in E. coli. Using small-angle X-ray scattering and X-ray crystallography, we show that this antagonist acts as a wedge. It prevents the large-scale domain closure that gives rise to the active signaling state. Guided by these results and the structures of open and closed glucose/galactose-binding protein, we designed and synthesized an antagonist composed of two linked glucose residues. These findings provide a blueprint for the design of new bacterial PBP inhibitors. Given the key role of PBPs in microbial physiology, we anticipate that PBP antagonists will have widespread uses as probes and antimicrobial agents. |
| | |
Authors:
|
M Jack Borrok; Yimin Zhu; Katrina T Forest; Laura L Kiessling |
Related Documents
:
|
18585346 - Lush shapes up for a starring role in olfaction. 21964726 - Jacalin interaction with human immunoglobulin a1 and bovine immunoglobulin g1: affinity... 3390206 - Direct photoaffinity labelling of binding proteins for beta-lactam antibiotics in rabbi... 115876 - Cephalosporin-sensitive penicillin-binding proteins of staphylococcus aureus and bacill... 2976136 - A novel two-site immunoradiometric assay for beta-endorphin using nitrocellulose as sol... 2769696 - The interaction of phenyldichloroarsine with erythrocytes. |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: ACS chemical biology Volume: 4 ISSN: 1554-8937 ISO Abbreviation: ACS Chem. Biol. Publication Date: 2009 Jun |
Date Detail:
|
Created Date: 2009-06-22 Completed Date: 2009-08-31 Revised Date: 2013-06-02 |
Medline Journal Info:
|
Nlm Unique ID: 101282906 Medline TA: ACS Chem Biol Country: United States |
Other Details:
|
Languages: eng Pagination: 447-56 Citation Subset: IM |
Affiliation:
|
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
3-O-Methylglucose
/
chemistry,
pharmacology* Binding Sites Crystallography, X-Ray Drug Design* Ligands Models, Molecular Molecular Conformation Periplasmic Binding Proteins / antagonists & inhibitors*, chemistry Structure-Activity Relationship |
| Grant Support | |
ID/Acronym/Agency:
|
GM059984/GM/NIGMS NIH HHS; GM07215/GM/NIGMS NIH HHS; R01 GM055984-11/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Ligands; 0/Periplasmic Binding Proteins; 146-72-5/3-O-Methylglucose |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Cucurbitane-Type Triterpenoids from the Stems of Cucumis melo.
Next Document: A tandem conjugate addition/cyclization protocol for the asymmetric synthesis of 2-aryl-4-aminotetra...