6GK9 | pdb_00006gk9

First-in-class allosteric inhibitors of bacterial IMPDHs.

(2019) Eur J Med Chem 167: 124-132

• PubMed: 30769241 Search on PubMed
• DOI: https://doi.org/10.1016/j.ejmech.2019.01.064
• Primary Citation of Related Structures:  
  6GJV, 6GK9


• PubMed Abstract: 
  

  Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class allosteric inhibitors of a bacterial IMPDH. These inhibitors were shown to counteract the activation by the natural positive effector, MgATP, and to block the enzyme in its apo conformation (low affinity for IMP). Our structural studies demonstrate the versatility of the Bateman domain to accommodate totally unrelated chemical scaffolds and pave the way for the development of allosteric inhibitors, an avenue little explored until now.

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Organizational Affiliation: 

Institut Pasteur, Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, CNRS UMR3523, 28 rue du Dr Roux, F-75015, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, F-75205, Paris, France.