3BHY

Crystal structure of human death associated protein kinase 3 (DAPK3) in complex with a beta-carboline ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.24 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.143 
  • R-Value Observed: 0.146 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

7,8-dichloro-1-oxo-beta-carbolines as a versatile scaffold for the development of potent and selective kinase inhibitors with unusual binding modes.

Huber, K.Brault, L.Fedorov, O.Gasser, C.Filippakopoulos, P.Bullock, A.N.Fabbro, D.Trappe, J.Schwaller, J.Knapp, S.Bracher, F.

(2012) J Med Chem 55: 403-413

  • DOI: https://doi.org/10.1021/jm201286z
  • Primary Citation of Related Structures:  
    3BHY, 3CXW, 3CY2

  • PubMed Abstract: 

    Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-β-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.


  • Organizational Affiliation

    Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Death-associated protein kinase 3283Homo sapiensMutation(s): 0 
Gene Names: DAPK3ZIPK
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O43293 (Homo sapiens)
Explore O43293 
Go to UniProtKB:  O43293
PHAROS:  O43293
GTEx:  ENSG00000167657 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO43293
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7CP
Query on 7CP

Download Ideal Coordinates CCD File 
C [auth A](4R)-7,8-dichloro-1',9-dimethyl-1-oxo-1,2,4,9-tetrahydrospiro[beta-carboline-3,4'-piperidine]-4-carbonitrile
C18 H18 Cl2 N4 O
XGUIMGJMQKZRGM-LLVKDONJSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
B [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.24 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.143 
  • R-Value Observed: 0.146 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 33.549α = 90
b = 90.68β = 100.45
c = 41.464γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2007-12-25
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-01-18
    Changes: Database references
  • Version 1.3: 2013-09-04
    Changes: Database references
  • Version 1.4: 2017-10-25
    Changes: Refinement description
  • Version 1.5: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description