7AKG

Crystal structure of STK17B with bound dovitinib

Summary for 7AKG

• Entry DOI: 10.2210/pdb7akg/pdb
• Descriptor: Serine/threonine-protein kinase 17B, 1,2-ETHANEDIOL, 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one, ... (4 entities in total)
• Functional Keywords: kinase, stk17b, inhibitor, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 38029.85

Authors

Chaikuad, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-09-30, release date: 2020-12-02, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.08 Å)