4MRO

Human GKRP bound to AMG-5980 and S6P

Summary for 4MRO

• Entry DOI: 10.2210/pdb4mro/pdb
• Related: 4MQU
• Descriptor: Glucokinase regulatory protein, 2-(4-{4-[(6-aminopyridin-3-yl)sulfonyl]piperazin-1-yl}phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol, D-SORBITOL-6-PHOSPHATE, ... (7 entities in total)
• Functional Keywords: sis domains, regulatory protein, glucokinase, phospho-fructose, transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): Q14397
• Total number of polymer chains: 2
• Total formula weight: 145403.00

Authors

St Jean, D.J.,Ashton, K.S.,Bartberger, M.D.,Chen, J.,Chmait, S.,Cupples, R.,Galbreath, E.,Helmering, J.,Jordan, S.R.,Liu, L.,Kunz, K.,Michelsen, K.,Nishimura, N.,Pennington, L.D.,Poon, S.F.,Sivits, G.,Stec, M.M.,Tamayo, N.,Van, G.,Yang, K.,Norman, M.H.,Fotsch, C.,LLoyd, D.J.,Hale, C. (deposition date: 2013-09-17, release date: 2014-05-07, Last modification date: 2024-04-03)

Primary citation

St Jean, D.J.,Ashton, K.S.,Bartberger, M.D.,Chen, J.,Chmait, S.,Cupples, R.,Galbreath, E.,Helmering, J.,Hong, F.T.,Jordan, S.R.,Liu, L.,Kunz, R.K.,Michelsen, K.,Nishimura, N.,Pennington, L.D.,Poon, S.F.,Reid, D.,Sivits, G.,Stec, M.M.,Tadesse, S.,Tamayo, N.,Van, G.,Yang, K.C.,Zhang, J.,Norman, M.H.,Fotsch, C.,Lloyd, D.J.,Hale, C.
Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles.
J.Med.Chem., 57:325-338, 2014

PubMed Abstract: In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.

PubMed: 24405213
DOI: 10.1021/jm4016747

Experimental method

X-RAY DIFFRACTION (2.2 Å)