6ZJF

Crystal structure of STK17B (DRAK2) in complex with AP-229


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

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

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.

(2020) J Med Chem 63: 14626-14646

  • DOI: https://doi.org/10.1021/acs.jmedchem.0c01174

  • 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 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.


  • Organizational Affiliation

    Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7264, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase 17B327Homo sapiensMutation(s): 0 
Gene Names: STK17BDRAK2
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O94768 (Homo sapiens)
Explore O94768 
Go to UniProtKB:  O94768
PHAROS:  O94768
GTEx:  ENSG00000081320 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO94768
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: P 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.349α = 90
b = 83.349β = 90
c = 114.259γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
iMOSFLMdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-07-29
    Type: Initial release
  • Version 1.1: 2021-01-13
    Changes: Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Database references, Refinement description