6I0M

Structure of human IMP dehydrogenase, isoform 2, bound to GDP

6I0M の概要

• エントリーDOI: 10.2210/pdb6i0m/pdb
• 分子名称: Inosine-5'-monophosphate dehydrogenase 2, GUANOSINE-5'-MONOPHOSPHATE, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: oxidoreductase, de novo guanine nucleotide biosynthesis, biosynthetic protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 116660.55

構造登録者

Buey, R.M.,Fernandez-Justel, D.,Revuelta, J.L. (登録日: 2018-10-26, 公開日: 2019-01-30, 最終更新日: 2024-01-24)

主引用文献

Fernandez-Justel, D.,Nunez, R.,Martin-Benito, J.,Jimeno, D.,Gonzalez-Lopez, A.,Soriano, E.M.,Revuelta, J.L.,Buey, R.M.
A Nucleotide-Dependent Conformational Switch Controls the Polymerization of Human IMP Dehydrogenases to Modulate their Catalytic Activity.
J. Mol. Biol., 431:956-969, 2019

PubMed Abstract: Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo GTP biosynthetic pathway and plays essential roles in cell proliferation. As a clinical target, IMPDH has been studied for decades, but it has only been within the last years that we are starting to understand the complexity of the mechanisms of its physiological regulation. Here, we report structural and functional insights into how adenine and guanine nucleotides control a conformational switch that modulates the assembly of the two human IMPDH enzymes into cytoophidia and allosterically regulates their catalytic activity. In vitro reconstituted micron-length cytoophidia-like structures show catalytic activity comparable to unassembled IMPDH but, in turn, are more resistant to GTP/GDP allosteric inhibition. Therefore, IMPDH cytoophidia formation facilitates the accumulation of high levels of guanine nucleotides when the cell requires it. Finally, we demonstrate that most of the IMPDH retinopathy-associated mutations abrogate GTP/GDP-induced allosteric inhibition and alter cytoophidia dynamics.

PubMed: 30664871
DOI: 10.1016/j.jmb.2019.01.020

実験手法

X-RAY DIFFRACTION (2.567 Å)