Wurm, Jan Philip and Sung, Sihyun and Kneuttinger, Andrea Christa and Hupfeld, Enrico and Sterner, Reinhard and Wilmanns, Matthias and Sprangers, Remco (2021) Molecular basis for the allosteric activation mechanism of the heterodimeric imidazole glycerol phosphate synthase complex. NATURE COMMUNICATIONS, 12 (1): 2748. ISSN 2041-1723,
Full text not available from this repository. (Request a copy)Abstract
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. The allosteric regulation of the bienzyme complex imidazole glycerol phosphate synthase (HisFH) remains to be elucidated. Here, the authors provide structural insights into the dynamic allosteric mechanism by which ligand binding to the cyclase and glutaminase active sites of HisFH regulate enzyme activation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GLUTAMINE AMIDOTRANSFERASE; CRYSTAL-STRUCTURE; STRUCTURAL INSIGHTS; MILLISECOND MOTIONS; THERMOTOGA-MARITIMA; ASSIGNMENT; BIENZYME; PROTEINS; COOPERATIVITY; SYNTHETASE; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Aug 2022 07:42 |
| Last Modified: | 29 Aug 2022 07:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46409 |
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