4OLH

Human GKRP Bound to AMG5106 and Sorbitol-6-Phosphate

Summary for 4OLH

• Entry DOI: 10.2210/pdb4olh/pdb
• Related: 4OHK 4OHM 4OHO 4OHP 4OP1 4OP2 4OP3
• Descriptor: Glucokinase Regulatory Protein, 2-(2-{4-[(6-aminopyridin-3-yl)sulfonyl]piperazin-1-yl}-3,3'-bipyridin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol, D-SORBITOL-6-PHOSPHATE, ... (7 entities in total)
• Functional Keywords: sis domain, regulatory protein, binds to and inhibits glucokinase, glucokinase, liver, carbohydrate binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q14397
• Total number of polymer chains: 2
• Total formula weight: 146069.21

Authors

Jordan, S.R.,Chmait, S. (deposition date: 2014-01-23, release date: 2014-07-23, Last modification date: 2023-09-20)

Primary citation

Hong, F.T.,Norman, M.H.,Ashton, K.S.,Bartberger, M.D.,Chen, J.,Chmait, S.,Cupples, R.,Fotsch, C.,Jordan, S.R.,Lloyd, D.J.,Sivits, G.,Tadesse, S.,Hale, C.,St Jean, D.J.
Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 4. Exploration of a novel binding pocket.
J.Med.Chem., 57:5949-5964, 2014

PubMed Abstract: Structure-activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N'-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 ("shelf region") as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50=0.005 μM and EC50=0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose.

PubMed: 25001129
DOI: 10.1021/jm5001979

Experimental method

X-RAY DIFFRACTION (2.4 Å)