4MQU

Human GKRP complexed to AMG-3969 and S6P

4MQU の概要

• エントリーDOI: 10.2210/pdb4mqu/pdb
• 関連するPDBエントリー: 4MRO
• 分子名称: 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)
• 機能のキーワード: sis domains, regulatory protein, binds fructose phosphates and glucokinase, transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (By similarity): Q14397
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 145479.10

構造登録者

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. (登録日: 2013-09-16, 公開日: 2014-05-07, 最終更新日: 2024-04-03)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.22 Å)