4MSU

Human GKRP bound to AMG-6861 and Sorbitol-6-phosphate

4MSU の概要

• エントリーDOI: 10.2210/pdb4msu/pdb
• 分子名称: Glucokinase regulatory protein, 1,1,1,3,3,3-hexafluoro-2-{4-[4-(thiophen-2-ylsulfonyl)piperazin-1-yl]phenyl}propan-2-ol, D-SORBITOL-6-PHOSPHATE, ... (7 entities in total)
• 機能のキーワード: sis domains, regulatory protein, glucokinase, phospho-fructose, sugar binding protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (By similarity): Q14397
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 145033.18

構造登録者

Ashton, K.S.,Andrews, K.L.,Bryan, M.C.,Chen, J.,Chen, K.,Chen, M.,Chmait, S.,Croghan, M.,Cupples, R.,Fotsch, C.,Helmering, J.,Jordan, S.R.,Kurzeja, R.J.,Michelsen, K.,Pennington, L.D.,Poon, S.F.,Sivits, G.,Van, G.,Vonderfecht, S.L.,Wahl, R.C.,Zhang, J.,Lloyd, D.J.,Hale, C.,St Jean, D.J. (登録日: 2013-09-18, 公開日: 2014-03-12, 最終更新日: 2024-02-28)

主引用文献

Ashton, K.S.,Andrews, K.L.,Bryan, M.C.,Chen, J.,Chen, K.,Chen, M.,Chmait, S.,Croghan, M.,Cupples, R.,Fotsch, C.,Helmering, J.,Jordan, S.R.,Kurzeja, R.J.,Michelsen, K.,Pennington, L.D.,Poon, S.F.,Sivits, G.,Van, G.,Vonderfecht, S.L.,Wahl, R.C.,Zhang, J.,Lloyd, D.J.,Hale, C.,St Jean, D.J.
Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept.
J.Med.Chem., 57:309-324, 2014

PubMed Abstract: Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.

PubMed: 24405172
DOI: 10.1021/jm4016735

実験手法

X-RAY DIFFRACTION (2.5 Å)