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-Structure paper
タイトル | IMPDH1 retinal variants control filament architecture to tune allosteric regulation. |
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ジャーナル・号・ページ | Nat Struct Mol Biol, Vol. 29, Issue 1, Page 47-58, Year 2022 |
掲載日 | 2022年1月10日 |
著者 | Anika L Burrell / Chuankai Nie / Meerit Said / Jacqueline C Simonet / David Fernández-Justel / Matthew C Johnson / Joel Quispe / Rubén M Buey / Jeffrey R Peterson / Justin M Kollman / |
PubMed 要旨 | Inosine-5'-monophosphate dehydrogenase (IMPDH), a key regulatory enzyme in purine nucleotide biosynthesis, dynamically assembles filaments in response to changes in metabolic demand. Humans have two ...Inosine-5'-monophosphate dehydrogenase (IMPDH), a key regulatory enzyme in purine nucleotide biosynthesis, dynamically assembles filaments in response to changes in metabolic demand. Humans have two isoforms: IMPDH2 filaments reduce sensitivity to feedback inhibition, while IMPDH1 assembly remains uncharacterized. IMPDH1 plays a unique role in retinal metabolism, and point mutants cause blindness. Here, in a series of cryogenic-electron microscopy structures we show that human IMPDH1 assembles polymorphic filaments with different assembly interfaces in extended and compressed states. Retina-specific splice variants introduce structural elements that reduce sensitivity to GTP inhibition, including stabilization of the extended filament form. Finally, we show that IMPDH1 disease mutations fall into two classes: one disrupts GTP regulation and the other has no effect on GTP regulation or filament assembly. These findings provide a foundation for understanding the role of IMPDH1 in retinal function and disease and demonstrate the diverse mechanisms by which metabolic enzyme filaments are allosterically regulated. |
リンク | Nat Struct Mol Biol / PubMed:35013599 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.4 - 3.9 Å |
構造データ | EMDB-24437, PDB-7rer: EMDB-24438: HUMAN IMPDH1 TREATED WITH ATP, IMP, AND NAD+; OCTAMER-CENTERED EMDB-24439, PDB-7rfe: EMDB-24440, PDB-7rff: EMDB-24441, PDB-7rfg: EMDB-24442, PDB-7rfh: EMDB-24443, PDB-7rfi: EMDB-24448, PDB-7rgd: EMDB-24450, PDB-7rgi: EMDB-24451, PDB-7rgl: EMDB-24452, PDB-7rgm: EMDB-24454, PDB-7rgq: |
化合物 | ChemComp-NAD: ChemComp-IMP: ChemComp-ATP: ChemComp-GTP: |
由来 |
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キーワード | OXIDOREDUCTASE / METABOLISM / FILAMENT / ALLOSTERY / ADENINE |