5CLP

Crystal Structure of CK2alpha with 3,4-dichlorophenethylamine bound

5CLP の概要

• エントリーDOI: 10.2210/pdb5clp/pdb
• 分子名称: Casein kinase II subunit alpha, 2-(3,4-dichlorophenyl)ethanamine, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: transferase, ck2alpha, ck2a, fragment based drug discovery, high concentration screening, selective atp competitive inhibitors, surface entrophy reduction
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P68400
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85203.49

構造登録者

Brear, P.,De Fusco, C.,Georgiou, K.H.,Spring, D.,Hyvonen, M. (登録日: 2015-07-16, 公開日: 2016-07-27, 最終更新日: 2024-01-10)

主引用文献

Brear, P.,De Fusco, C.,Hadje Georgiou, K.,Francis-Newton, N.J.,Stubbs, C.J.,Sore, H.F.,Venkitaraman, A.R.,Abell, C.,Spring, D.R.,Hyvonen, M.
Specific inhibition of CK2 alpha from an anchor outside the active site.
Chem Sci, 7:6839-6845, 2016

PubMed Abstract: The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with a of 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2α a novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.

PubMed: 28451126
DOI: 10.1039/c6sc02335e

実験手法

X-RAY DIFFRACTION (1.684 Å)