ArticleThe journal of physical chemistry. B2011
Nature of allosteric inhibition in glutamate racemase: discovery and characterization of a cryptic inhibitory pocket using atomistic MD simulations and pKa calculations.
Article in The journal of physical chemistry. B, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 24 citations in OpenAlex.
- Recent computational advances in the identification of cryptic binding sites for drug discovery.Bioinformatics advances · 2025Review
- MptpA Kinetics Enhanced by Allosteric Control of an Active Conformation.Journal of molecular biology · 2022Article
- Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition.Chemical Society reviews · 2021Review
- Integrating Experimental and In Silico HTS in the Discovery of Inhibitors of Protein-Nucleic Acid Interactions.Methods in enzymology · 2018Article
- Systematic exploration of multiple drug binding sites.Journal of cheminformatics · 2017Article
- Biochemical Characterization of Glutamate Racemase-A New Candidate Drug Target against Burkholderia cenocepacia Infections.PloS one · 2016Article
- Biosynthesis of a Novel Glutamate Racemase Containing a Site-Specific 7-Hydroxycoumarin Amino Acid: Enzyme-Ligand Promiscuity Revealed at the Atomistic Level.ACS central science · 2015Article
- Glutamate Racemase Mutants of Bacillus anthracis.Journal of bacteriology · 2015Article
- Flooding enzymes: quantifying the contributions of interstitial water and cavity shape to ligand binding using extended linear response free energy calculations.Journal of chemical information and modeling · 2013Article
- Molecular mechanism of allosteric communication in Hsp70 revealed by molecular dynamics simulations.PLoS computational biology · 2012Article
- New developments in vaccines, inhibitors of anthrax toxins, and antibiotic therapeutics for Bacillus anthracis.Current medicinal chemistry · 2011Review
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Enzyme inhibition via allostery, in which the ligand binds remotely from the active site, is a poorly understood phenomenon and represents a significant challenge to structure-based drug design. Dipicolinic acid (DPA), a major component of Bacillus spores, is shown to inhibit glutamate racemase from Bacillus anthracis , a monosubstrate/monoproduct enzyme, in a novel allosteric fashion. Glutamate racemase has long been considered an important drug target for its integral role in bacterial cell wall synthesis. The DPA binding mode was predicted via multiple docking studies and validated via site-directed mutagenesis at the binding locus, while the mechanism of inhibition was elucidated with a combination of Blue Native polyacrylamide gel electrophoresis, molecular dynamics simulations, and free energy and pK(a) calculations. Inhibition by DPA not only reveals a novel cryptic binding site but also represents a form of allosteric regulation that exploits the interplay between enzyme conformational changes, fluctuations in the pK(a) values of buried residues and catalysis. The potential for future drug development is discussed.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.