3PSC

Bovine GRK2 in complex with Gbetagamma subunits


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.67 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.225 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Molecular Mechanism of Selectivity among G Protein-Coupled Receptor Kinase 2 Inhibitors.

Thal, D.M.Yeow, R.Y.Schoenau, C.Huber, J.Tesmer, J.J.

(2011) Mol Pharmacol 80: 294-303

  • DOI: https://doi.org/10.1124/mol.111.071522
  • Primary Citation of Related Structures:  
    3PSC, 3PVU, 3PVW

  • PubMed Abstract: 

    G protein-coupled receptors (GPCRs) are key regulators of cell physiology and control processes ranging from glucose homeostasis to contractility of the heart. A major mechanism for the desensitization of activated GPCRs is their phosphorylation by GPCR kinases (GRKs). Overexpression of GRK2 is strongly linked to heart failure, and GRK2 has long been considered a pharmaceutical target for the treatment of cardiovascular disease. Several lead compounds developed by Takeda Pharmaceuticals show high selectivity for GRK2 and therapeutic potential for the treatment of heart failure. To understand how these drugs achieve their selectivity, we determined crystal structures of the bovine GRK2-Gβγ complex in the presence of two of these inhibitors. Comparison with the apoGRK2-Gβγ structure demonstrates that the compounds bind in the kinase active site in a manner similar to that of the AGC kinase inhibitor balanol. Both balanol and the Takeda compounds induce a slight closure of the kinase domain, the degree of which correlates with the potencies of the inhibitors. Based on our crystal structures and homology modeling, we identified five amino acids surrounding the inhibitor binding site that we hypothesized could contribute to inhibitor selectivity. However, our results indicate that these residues are not major determinants of selectivity among GRK subfamilies. Rather, selectivity is achieved by the stabilization of a unique inactive conformation of the GRK2 kinase domain.


  • Organizational Affiliation

    Life Sciences Institute, University of Michigan, 210 Washtenaw Ave., Room 3425, Ann Arbor, MI 48109, USA. tesmerjj@umich.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-adrenergic receptor kinase 1695Bos taurusMutation(s): 1 
Gene Names: ADRBK1GRK2
EC: 2.7.11.15
UniProt
Find proteins for P21146 (Bos taurus)
Explore P21146 
Go to UniProtKB:  P21146
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21146
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1340Bos taurusMutation(s): 0 
Gene Names: GNB1
UniProt
Find proteins for P62871 (Bos taurus)
Explore P62871 
Go to UniProtKB:  P62871
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP62871
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2C [auth G]74Bos taurusMutation(s): 0 
Gene Names: GNG2
UniProt
Find proteins for P63212 (Bos taurus)
Explore P63212 
Go to UniProtKB:  P63212
Entity Groups  
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UniProt GroupP63212
Sequence Annotations
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  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CMT
Query on CMT
C [auth G]L-PEPTIDE LINKINGC4 H9 N O2 SCYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.67 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.225 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 187.928α = 90
b = 73.152β = 115.42
c = 122.78γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-06-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-07-27
    Changes: Database references
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description