Molecular basis for the allosteric activation mechanism of the heterodimeric imidazole glycerol phosphate synthase complex.
Allosteric Regulation
Aminohydrolases
/ chemistry
Binding Sites
Catalysis
Catalytic Domain
Crystallography, X-Ray
Glutamine
/ metabolism
Hydrolysis
Imidazoles
/ metabolism
Magnetic Resonance Spectroscopy
Multienzyme Complexes
Mutation
Protein Conformation
Ribonucleotides
/ metabolism
Thermotoga maritima
/ enzymology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 05 2021
12 05 2021
Historique:
received:
05
10
2020
accepted:
07
04
2021
entrez:
13
5
2021
pubmed:
14
5
2021
medline:
29
5
2021
Statut:
epublish
Résumé
Imidazole glycerol phosphate synthase (HisFH) is a heterodimeric bienzyme complex operating at a central branch point of metabolism. HisFH is responsible for the HisH-catalyzed hydrolysis of glutamine to glutamate and ammonia, which is then used for a cyclase reaction by HisF. The HisFH complex is allosterically regulated but the underlying mechanism is not well understood. Here, we elucidate the molecular basis of the long range, allosteric activation of HisFH. We establish that the catalytically active HisFH conformation is only formed when the substrates of both HisH and HisF are bound. We show that in this conformation an oxyanion hole in the HisH active site is established, which rationalizes the observed 4500-fold allosteric activation compared to the inactive conformation. In solution, the inactive and active conformations are in a dynamic equilibrium and the HisFH turnover rates correlate with the population of the active conformation, which is in accordance with the ensemble model of allostery.
Identifiants
pubmed: 33980881
doi: 10.1038/s41467-021-22968-6
pii: 10.1038/s41467-021-22968-6
pmc: PMC8115485
doi:
Substances chimiques
Imidazoles
0
Multienzyme Complexes
0
Ribonucleotides
0
Glutamine
0RH81L854J
N(1)-((5'-phosphoribulosyl)formimino)-5-aminoimidazo-4-carboxamide ribonucleotide
36244-86-7
imidazole glycerol phosphate synthase
EC 3.5.1.-
Aminohydrolases
EC 3.5.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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