Journal article
Decrypting a cryptic allosteric pocket in H. pylori glutamate racemase
Communications chemistry, Vol.4(1), pp.1-13
12/10/2021
DOI: 10.1038/s42004-021-00605-z
PMCID: PMC9169614
PMID: 35673630
Abstract
One of our greatest challenges in drug design is targeting cryptic allosteric pockets in enzyme targets. Drug leads that do bind to these cryptic pockets are often discovered during HTS campaigns, and the mechanisms of action are rarely understood. Nevertheless, it is often the case that the allosteric pocket provides the best option for drug development against a given target. In the current studies we present a successful way forward in rationally exploiting the cryptic allosteric pocket of H. pylori glutamate racemase, an essential enzyme in this pathogen's life cycle. A wide range of computational and experimental methods are employed in a workflow leading to the discovery of a series of natural product allosteric inhibitors which occupy the allosteric pocket of this essential racemase. The confluence of these studies reveals a fascinating source of the allosteric inhibition, which centers on the abolition of essential monomer-monomer coupled motion networks.
Protein-ligand binding can induce the formation of cryptic allosteric pockets not found in the unbound protein, but predicting this computationally can be challenging. Here a combined computational and experimental workflow identifies ligands for H. pyloriglutamate racemase, finding that coupled dynamics of the enzyme dimer are dampened by ligand binding.
Details
- Title: Subtitle
- Decrypting a cryptic allosteric pocket in H. pylori glutamate racemase
- Creators
- Pratik Rajesh Chheda - University of IowaGrant T. Cooling - University of IowaSondra F. Dean - University of IowaJonah Propp - University of IowaKathryn F. Hobbs - University of IowaM. Ashley Spies - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Communications chemistry, Vol.4(1), pp.1-13
- DOI
- 10.1038/s42004-021-00605-z
- PMID
- 35673630
- PMCID
- PMC9169614
- NLM abbreviation
- Commun Chem
- ISSN
- 2399-3669
- eISSN
- 2399-3669
- Publisher
- NATURE PORTFOLIO
- Number of pages
- 13
- Grant note
- T32 GM008365 / University of Iowa Center for Biocatalysis and Bioprocessing R01-GM09737; R01GM138471 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 12/10/2021
- Academic Unit
- Stead Family Department of Pediatrics; Pharmaceutical Sciences and Experimental Therapeutics; Biochemistry and Molecular Biology; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984288717802771
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