6Y6F

Crystal structure of STK17B (DRAK2) in complex with PKIS43

6Y6F の概要

• エントリーDOI: 10.2210/pdb6y6f/pdb
• 分子名称: Serine/threonine-protein kinase 17B, 2-[6-(4-methylsulfanylphenyl)thieno[3,2-d]pyrimidin-4-yl]sulfanylethanoic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: kinase, kinase inhibitor, pkis, drak2, chemical probe, structural genomics, structural genomics consortium, sgc, transferase
• 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: 37923.82

構造登録者

Chaikuad, A.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Drewry, D.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2020-02-26, 公開日: 2020-03-11, 最終更新日: 2024-01-24)

主引用文献

Picado, A.,Chaikuad, A.,Wells, C.I.,Shrestha, S.,Zuercher, W.J.,Pickett, J.E.,Kwarcinski, F.E.,Sinha, P.,de Silva, C.S.,Zutshi, R.,Liu, S.,Kannan, N.,Knapp, S.,Drewry, D.H.,Willson, T.M.
A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation.
J.Med.Chem., 63:14626-14646, 2020

PubMed Abstract: STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine (), a high-quality chemical probe for this understudied "dark" kinase. is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine () was identified as a negative control compound. The >100-fold lower activity of on STK17B was attributed to the reduced basicity of its pyrimidine N1.

PubMed: 33215924
DOI: 10.1021/acs.jmedchem.0c01174

実験手法

X-RAY DIFFRACTION (1.98 Å)