4OP1

GKRP bound to AMG0556 and Sorbitol-6-Phosphate

Summary for 4OP1

• Entry DOI: 10.2210/pdb4op1/pdb
• Related: 4OHK 4OHM 4OHO 4OHP 4OLH 4OP2 4OP3
• Descriptor: Glucokinase Regulatory Protein, (2S)-2-(6-{5-[(6-aminopyridin-3-yl)sulfonyl]thiophen-2-yl}-5-chloropyridin-3-yl)-1,1,1-trifluoropropan-2-ol, D-SORBITOL-6-PHOSPHATE, ... (7 entities in total)
• Functional Keywords: sis domain containing protein, regulatory protein that binds to and inhibits glucokinase activity, glucokinase, liver, carbohydrate binding protein, carbohydrate binding protein-inhibitor complex, carbohydrate binding protein/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q14397
• Total number of polymer chains: 2
• Total formula weight: 145902.83

Authors

Jordan, S.R.,Chmait, S. (deposition date: 2014-02-04, release date: 2014-07-30, Last modification date: 2023-09-20)

Primary citation

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describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group.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

Experimental method

X-RAY DIFFRACTION (2.39 Å)