PDBsum entry 6y6h

Transferase

PDB id: 6y6h

Contents

Protein chain

292 a.a.

Ligands

OBW

EDO ×5

Waters ×172

References listed in PDB file

Key reference

• Title: A chemical probe for dark kinase stk17b derives its potency and high selectivity through a unique p-Loop conformation.
• Authors: A.Picado, A.Chaikuad, C.I.Wells, S.Shrestha, W.J.Zuercher, J.E.Pickett, F.E.Kwarcinski, P.Sinha, C.S.De silva, R.Zutshi, S.Liu, N.Kannan, S.Knapp, D.H.Drewry, T.M.Willson.
• Ref.: J Med Chem, 2020, 63, 14626-14646. [DOI no: 10.1021/acs.jmedchem.0c01174]
• PubMed id: 33215924

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 SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied "dark" kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s 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 SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1.