4MSU

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

Summary for 4MSU

• Entry DOI: 10.2210/pdb4msu/pdb
• Descriptor: 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)
• Functional Keywords: sis domains, regulatory protein, glucokinase, phospho-fructose, sugar binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): Q14397
• Total number of polymer chains: 2
• Total formula weight: 145033.18

Authors

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. (deposition date: 2013-09-18, release date: 2014-03-12, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)