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Communication between the active site and the allosteric site in class A beta-lactamases

Paper ID Volume ID Publish Year Pages File Format Full-Text
15148 1382 2013 10 PDF Available
Title
Communication between the active site and the allosteric site in class A beta-lactamases
Abstract

Bacterial production of beta-lactamases, which hydrolyze beta-lactam type antibiotics, is a common antibiotic resistance mechanism. Antibiotic resistance is a high priority intervention area and one strategy to overcome resistance is to administer antibiotics with beta-lactamase inhibitors in the treatment of infectious diseases. Unfortunately, beta-lactamases are evolving at a rapid pace with new inhibitor resistant mutants emerging every day, driving the design and development of novel beta-lactamase inhibitors. Here, we examined the inhibitor recognition mechanism of two common beta-lactamases using molecular dynamics simulations. Binding of beta-lactamase inhibitor protein (BLIP) caused changes in the flexibility of regions away from the binding site. One of these regions was the H10 helix, which was previously identified to form a lid over an allosteric inhibitor binding site. Closer examination of the H10 helix using sequence and structure comparisons with other beta-lactamases revealed the presence of a highly conserved Trp229 residue, which forms a stacking interaction with two conserved proline residues. Molecular dynamics simulations on the Trp229Ala mutants of TEM-1 and SHV-1 resulted in decreased stability in the apo form, possibly due to loss of the stacking interaction as a result of the mutation. The mutant TEM-1 beta-lactamase had higher H10 fluctuations in the presence of BLIP, higher affinity to BLIP and higher cross-correlations with BLIP. Our results suggest that the H10 helix and specifically W229 are important modulators of the allosteric communication between the active site and the allosteric site.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Molecular dynamics simulations on different beta-lactamase–BLIP systems were performed. ► Comparison of the simulations revealed differences in a site previously identified to bind an allosteric inhibitor. ► W229 residue of the allosteric site was found to be highly conserved. ► Mutation of W229 results in enhanced ligand binding and higher correlations between beta-lactamase and BLIP.

Keywords
BLIP, beta-lactamase inhibitor protein; MD, molecular dynamics; MSF, mean square fluctuations; RMSD, root mean square deviation; VMD, visual molecular dynamicsBeta-lactamase; Ligand binding; Molecular dynamics simulations; Binding free energy; Allostery
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Publisher
Database: Elsevier - ScienceDirect
Journal: Computational Biology and Chemistry - Volume 43, April 2013, Pages 1–10
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us