7RFE

HUMAN IMPDH1 TREATED WITH GTP, IMP, AND NAD+; INTERFACE-CENTERED

7RFE の概要

• エントリーDOI: 10.2210/pdb7rfe/pdb
• EMDBエントリー: 24439
• 分子名称: Inosine-5'-monophosphate dehydrogenase 1, GUANOSINE-5'-TRIPHOSPHATE, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: metabolism, filament, allostery, adenine, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 450906.19

構造登録者

Burrell, A.L.,Kollman, J.M. (登録日: 2021-07-14, 公開日: 2022-01-12, 最終更新日: 2024-06-05)

主引用文献

Burrell, A.L.,Nie, C.,Said, M.,Simonet, J.C.,Fernandez-Justel, D.,Johnson, M.C.,Quispe, J.,Buey, R.M.,Peterson, J.R.,Kollman, J.M.
IMPDH1 retinal variants control filament architecture to tune allosteric regulation.
Nat.Struct.Mol.Biol., 29:47-58, 2022

PubMed Abstract: 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.

PubMed: 35013599
DOI: 10.1038/s41594-021-00706-2

実験手法

ELECTRON MICROSCOPY (2.6 Å)