PDBsum entry 6y6h

Transferase

PDB id: 6y6h

Contents

Protein chain

292 a.a.

Ligands

OBW

EDO ×5

Waters ×172

PDB id:

6y6h

Name:

Transferase

Title:

Crystal structure of stk17b (drak2) in complex with unc-ap-194 probe

Structure:

Serine/threonine-protein kinase 17b. Chain: a. Synonym: dap kinase-related apoptosis-inducing protein kinase 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: stk17b, drak2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: -r3-prare2.

Resolution:

1.95Å R-factor: 0.183 R-free: 0.212

Authors:

A.Chaikuad,C.H.Arrowsmith,A.M.Edwards,C.Bountra,D.Drewry,S.Knapp, Structural Genomics Consortium (Sgc)

Key ref:

A.Picado et al. (2020). 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. PubMed id: 33215924 DOI: 10.1021/acs.jmedchem.0c01174

Date:

26-Feb-20 Release date: 11-Mar-20

Protein chain

O94768  (ST17B_HUMAN) -  Serine/threonine-protein kinase 17B from Homo sapiens

Seq: 372 a.a.

Struc: 292 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.0c01174

J Med Chem 63:14626-14646 (2020)

PubMed id: 33215924

A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation.

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.

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.