First-in-class allosteric inhibitors of bacterial IMPDHs.
Allosteric inhibitor
Bateman domain
Chemical library screening
IMPDH
Nucleotide metabolism
Quaternary structure
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
01 Apr 2019
01 Apr 2019
Historique:
received:
07
08
2018
revised:
10
10
2018
accepted:
27
01
2019
pubmed:
16
2
2019
medline:
19
4
2019
entrez:
16
2
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30769241
pii: S0223-5234(19)30084-4
doi: 10.1016/j.ejmech.2019.01.064
pii:
doi:
Substances chimiques
Apoproteins
0
Bacterial Proteins
0
Enzyme Inhibitors
0
Small Molecule Libraries
0
Adenosine Triphosphate
8L70Q75FXE
IMP Dehydrogenase
EC 1.1.1.205
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
124-132Informations de copyright
Copyright © 2019 Elsevier Masson SAS. All rights reserved.