8RU8

A crystal form of a human CDK2-CDK7 chimera

8RU8 の概要

• エントリーDOI: 10.2210/pdb8ru8/pdb
• 分子名称: Cyclin-dependent kinase 2, (3R,4R)-4-[[[7-[(phenylmethyl)amino]-3-propan-2-yl-pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol (3 entities in total)
• 機能のキーワード: cyclin dependent kinase 7, serine/threonine kinase, atp binding, cell cycle kinase, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35166.86

構造登録者

Mukherjee, M.,Cleasby, A. (登録日: 2024-01-30, 公開日: 2024-06-26, 最終更新日: 2024-08-21)

主引用文献

Mukherjee, M.,Day, P.J.,Laverty, D.,Bueren-Calabuig, J.A.,Woodhead, A.J.,Griffiths-Jones, C.,Hiscock, S.,East, C.,Boyd, S.,O'Reilly, M.
Protein engineering enables a soakable crystal form of human CDK7 primed for high-throughput crystallography and structure-based drug design.
Structure, 32:1040-1048.e3, 2024

PubMed Abstract: Cyclin dependent kinase 7 (CDK7) is an important therapeutic kinase best known for its dual role in cell cycle regulation and gene transcription. Here, we describe the application of protein engineering to generate constructs leading to high resolution crystal structures of human CDK7 in both active and inactive conformations. The active state of the kinase was crystallized by incorporation of an additional surface residue mutation (W132R) onto the double phosphomimetic mutant background (S164D and T170E) that yielded the inactive kinase structure. A novel back-soaking approach was developed to determine crystal structures of several clinical and pre-clinical inhibitors of this kinase, demonstrating the potential utility of the crystal system for structure-based drug design (SBDD). The crystal structures help to rationalize the mode of inhibition and the ligand selectivity profiles versus key anti-targets. The protein engineering approach described here illustrates a generally applicable strategy for structural enablement of challenging molecular targets.

PubMed: 38870939
DOI: 10.1016/j.str.2024.05.011

実験手法

X-RAY DIFFRACTION (1.51 Å)