5LQF

CDK1/CyclinB1/CKS2 in complex with NU6102

5LQF の概要

• エントリーDOI: 10.2210/pdb5lqf/pdb
• 分子名称: Cyclin-dependent kinase 1, G2/mitotic-specific cyclin-B1, Cyclin-dependent kinases regulatory subunit 2, ... (5 entities in total)
• 機能のキーワード: cdk1 cyclin b cks2 cell cycle nu6102, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus: P06493; Cytoplasm: P14635
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 153233.71

構造登録者

Coxon, C.R.,Anscombe, E.,Harnor, S.J.,Martin, M.P.,Carbain, B.J.,Hardcastle, I.R.,Harlow, L.K.,Korolchuk, S.,Matheson, C.J.,Noble, M.E.,Newell, D.R.,Turner, D.M.,Sivaprakasam, M.,Wang, L.Z.,Wong, C.,Golding, B.T.,Griffin, R.J.,Endicott, J.A.,Cano, C. (登録日: 2016-08-17, 公開日: 2017-01-11, 最終更新日: 2024-01-10)

主引用文献

Coxon, C.R.,Anscombe, E.,Harnor, S.J.,Martin, M.P.,Carbain, B.,Golding, B.T.,Hardcastle, I.R.,Harlow, L.K.,Korolchuk, S.,Matheson, C.J.,Newell, D.R.,Noble, M.E.,Sivaprakasam, M.,Tudhope, S.J.,Turner, D.M.,Wang, L.Z.,Wedge, S.R.,Wong, C.,Griffin, R.J.,Endicott, J.A.,Cano, C.
Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines.
J. Med. Chem., 60:1746-1767, 2017

PubMed Abstract: Purines and related heterocycles substituted at C-2 with 4'-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1'-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.

PubMed: 28005359
DOI: 10.1021/acs.jmedchem.6b01254

実験手法

X-RAY DIFFRACTION (2.06 Å)