4OP2

GKRP bound to AMG-0471 and Sorbitol-6-Phosphate

4OP2 の概要

• エントリーDOI: 10.2210/pdb4op2/pdb
• 関連するPDBエントリー: 4OHK 4OHM 4OHO 4OHP 4OLH 4OP1 4OP3
• 分子名称: Glucokinase Regulatory Protein, (2S)-2-{4'-[(6-aminopyridin-3-yl)sulfonyl]biphenyl-4-yl}-1,1,1-trifluoropropan-2-ol, D-SORBITOL-6-PHOSPHATE, ... (7 entities in total)
• 機能のキーワード: sis domain containing protein, binds to and inhibits glucokinase, glucokinase, carbohydrate binding protein-inhibitor complex, carbohydrate binding protein/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : Q14397
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 145662.17

構造登録者

Jordan, S.R.,Chmait, S. (登録日: 2014-02-04, 公開日: 2014-07-30, 最終更新日: 2023-09-20)

主引用文献

Tamayo, N.A.,Norman, M.H.,Bartberger, M.D.,Hong, F.T.,Bo, Y.,Liu, L.,Nishimura, N.,Yang, K.C.,Tadesse, S.,Fotsch, C.,Chen, J.,Chmait, S.,Cupples, R.,Hale, C.,Jordan, S.R.,Lloyd, D.J.,Sivits, G.,Van, G.,St Jean, D.J.
Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.
J.Med.Chem., 58:4462-4482, 2015

PubMed Abstract: The glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.

PubMed: 25914941
DOI: 10.1021/jm5018175

実験手法

X-RAY DIFFRACTION (2.24 Å)