Deciphering the allosteric regulation of mycobacterial inosine-5'-monophosphate dehydrogenase.
IMP Dehydrogenase
/ metabolism
Allosteric Regulation
Guanosine Triphosphate
/ metabolism
Cryoelectron Microscopy
Catalytic Domain
Models, Molecular
Bacterial Proteins
/ metabolism
Guanosine Pentaphosphate
/ metabolism
Inosine Monophosphate
/ metabolism
Protein Binding
Adenosine Triphosphate
/ metabolism
Mycobacterium smegmatis
/ enzymology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Aug 2024
06 Aug 2024
Historique:
received:
04
01
2024
accepted:
24
07
2024
medline:
7
8
2024
pubmed:
7
8
2024
entrez:
6
8
2024
Statut:
epublish
Résumé
Allosteric regulation of inosine 5'-monophosphate dehydrogenase (IMPDH), an essential enzyme of purine metabolism, contributes to the homeostasis of adenine and guanine nucleotides. However, the precise molecular mechanism of IMPDH regulation in bacteria remains unclear. Using biochemical and cryo-EM approaches, we reveal the intricate molecular mechanism of the IMPDH allosteric regulation in mycobacteria. The enzyme is inhibited by both GTP and (p)ppGpp, which bind to the regulatory CBS domains and, via interactions with basic residues in hinge regions, lock the catalytic core domains in a compressed conformation. This results in occlusion of inosine monophosphate (IMP) substrate binding to the active site and, ultimately, inhibition of the enzyme. The GTP and (p)ppGpp allosteric effectors bind to their dedicated sites but stabilize the compressed octamer by a common mechanism. Inhibition is relieved by the competitive displacement of GTP or (p)ppGpp by ATP allowing IMP-induced enzyme expansion. The structural knowledge and mechanistic understanding presented here open up new possibilities for the development of allosteric inhibitors with antibacterial potential.
Identifiants
pubmed: 39107302
doi: 10.1038/s41467-024-50933-6
pii: 10.1038/s41467-024-50933-6
doi:
Substances chimiques
IMP Dehydrogenase
EC 1.1.1.205
Guanosine Triphosphate
86-01-1
Bacterial Proteins
0
Guanosine Pentaphosphate
38918-96-6
Inosine Monophosphate
131-99-7
Adenosine Triphosphate
8L70Q75FXE
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6673Informations de copyright
© 2024. The Author(s).
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