4PNK

G protein-coupled receptor kinase 2 in complex with GSK180736A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.56 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.194 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Identification and structure-function analysis of subfamily selective g protein-coupled receptor kinase inhibitors.

Homan, K.T.Larimore, K.M.Elkins, J.M.Szklarz, M.Knapp, S.Tesmer, J.J.

(2015) ACS Chem Biol 10: 310-319

  • DOI: https://doi.org/10.1021/cb5006323
  • Primary Citation of Related Structures:  
    4PNI, 4PNK

  • PubMed Abstract: 

    Selective inhibitors of individual subfamilies of G protein-coupled receptor kinases (GRKs) would serve as useful chemical probes as well as leads for therapeutic applications ranging from heart failure to Parkinson's disease. To identify such inhibitors, differential scanning fluorimetry was used to screen a collection of known protein kinase inhibitors that could increase the melting points of the two most ubiquitously expressed GRKs: GRK2 and GRK5. Enzymatic assays on 14 of the most stabilizing hits revealed that three exhibit nanomolar potency of inhibition for individual GRKs, some of which exhibiting orders of magnitude selectivity. Most of the identified compounds can be clustered into two chemical classes: indazole/dihydropyrimidine-containing compounds that are selective for GRK2 and pyrrolopyrimidine-containing compounds that potently inhibit GRK1 and GRK5 but with more modest selectivity. The two most potent inhibitors representing each class, GSK180736A and GSK2163632A, were cocrystallized with GRK2 and GRK1, and their atomic structures were determined to 2.6 and 1.85 Å spacings, respectively. GSK180736A, developed as a Rho-associated, coiled-coil-containing protein kinase inhibitor, binds to GRK2 in a manner analogous to that of paroxetine, whereas GSK2163632A, developed as an insulin-like growth factor 1 receptor inhibitor, occupies a novel region of the GRK active site cleft that could likely be exploited to achieve more selectivity. However, neither compound inhibits GRKs more potently than their initial targets. This data provides the foundation for future efforts to rationally design even more potent and selective GRK inhibitors.


  • Organizational Affiliation

    Life Sciences Institute and the Departments of Pharmacology and Biological Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-adrenergic receptor kinase 1689Homo sapiensMutation(s): 0 
Gene Names: ADRBK1BARKBARK1GRK2
EC: 2.7.11.15
UniProt & NIH Common Fund Data Resources
Find proteins for P25098 (Homo sapiens)
Explore P25098 
Go to UniProtKB:  P25098
PHAROS:  P25098
GTEx:  ENSG00000173020 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25098
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-1340Homo sapiensMutation(s): 0 
Gene Names: GNB1
UniProt & NIH Common Fund Data Resources
Find proteins for P62873 (Homo sapiens)
Explore P62873 
Go to UniProtKB:  P62873
PHAROS:  P62873
GTEx:  ENSG00000078369 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP62873
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]71Bos taurusMutation(s): 1 
Gene Names: GNG2
UniProt
Find proteins for P63212 (Bos taurus)
Explore P63212 
Go to UniProtKB:  P63212
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP63212
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KZQ
Query on KZQ

Download Ideal Coordinates CCD File 
D [auth A](4S)-4-(4-fluorophenyl)-N-(2H-indazol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
C19 H16 F N5 O2
HEAIGWIZTYAQTC-KRWDZBQOSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.56 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.194 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 61.435α = 90
b = 241.398β = 90
c = 212.526γ = 90
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesHL071818 and HL086865
American Heart AssociationUnited StatesN014938

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-08
    Type: Initial release
  • Version 1.1: 2014-12-24
    Changes: Database references
  • Version 1.2: 2015-01-28
    Changes: Database references
  • Version 1.3: 2017-09-06
    Changes: Author supporting evidence, Derived calculations, Other, Source and taxonomy
  • Version 1.4: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.5: 2023-12-27
    Changes: Data collection, Database references, Refinement description