4MQU
Human GKRP complexed to AMG-3969 and S6P
Summary for 4MQU
| Entry DOI | 10.2210/pdb4mqu/pdb |
| Related | 4MRO |
| Descriptor | Glucokinase regulatory protein, 2-{4-[(2S)-4-[(6-aminopyridin-3-yl)sulfonyl]-2-(prop-1-yn-1-yl)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, binds fructose phosphates and glucokinase, transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus (By similarity): Q14397 |
| Total number of polymer chains | 2 |
| Total formula weight | 145479.10 |
| 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. (deposition date: 2013-09-16, 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 Cited by 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: 24405213DOI: 10.1021/jm4016747 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.22 Å) |
Structure validation
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