4Z87

Structure of the IMP dehydrogenase from Ashbya gossypii bound to GDP

4Z87 の概要

• エントリーDOI: 10.2210/pdb4z87/pdb
• 分子名称: Inosine-5'-monophosphate dehydrogenase, GUANOSINE-5'-MONOPHOSPHATE, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: imp dehydrgoenase, bateman domain, oxidoreductase
• 由来する生物種: Ashbya gossypii (strain ATCC 10895)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 234398.66

構造登録者

Buey, R.M.,de Pereda, J.M.,Revuelta, J.L. (登録日: 2015-04-08, 公開日: 2015-11-25, 最終更新日: 2024-01-10)

主引用文献

Buey, R.M.,Ledesma-Amaro, R.,Velazquez-Campoy, A.,Balsera, M.,Chagoyen, M.,de Pereda, J.M.,Revuelta, J.L.
Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases.
Nat Commun, 6:8923-8923, 2015

PubMed Abstract: Inosine-5'-monophosphate dehydrogenase (IMPDH) plays key roles in purine nucleotide metabolism and cell proliferation. Although IMPDH is a widely studied therapeutic target, there is limited information about its physiological regulation. Using Ashbya gossypii as a model, we describe the molecular mechanism and the structural basis for the allosteric regulation of IMPDH by guanine nucleotides. We report that GTP and GDP bind to the regulatory Bateman domain, inducing octamers with compromised catalytic activity. Our data suggest that eukaryotic and prokaryotic IMPDHs might have developed different regulatory mechanisms, with GTP/GDP inhibiting only eukaryotic IMPDHs. Interestingly, mutations associated with human retinopathies map into the guanine nucleotide-binding sites including a previously undescribed non-canonical site and disrupt allosteric inhibition. Together, our results shed light on the mechanisms of the allosteric regulation of enzymes mediated by Bateman domains and provide a molecular basis for certain retinopathies, opening the door to new therapeutic approaches.

PubMed: 26558346
DOI: 10.1038/ncomms9923

実験手法

X-RAY DIFFRACTION (2.25 Å)