6PJX

Crystal Structure of G Protein-Coupled Receptor Kinase 5 (GRK5) in Complex with Calmodulin (CaM)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 

Starting Model: experimental
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This is version 1.3 of the entry. See complete history


Literature

Structure of a GRK5-Calmodulin Complex Reveals Molecular Mechanism of GRK Activation and Substrate Targeting.

Komolov, K.E.Sulon, S.M.Bhardwaj, A.van Keulen, S.C.Duc, N.M.Laurinavichyute, D.K.Lou, H.J.Turk, B.E.Chung, K.Y.Dror, R.O.Benovic, J.L.

(2021) Mol Cell 81: 323

  • DOI: https://doi.org/10.1016/j.molcel.2020.11.026
  • Primary Citation of Related Structures:  
    6PJX

  • PubMed Abstract: 

    The phosphorylation of G protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) facilitates arrestin binding and receptor desensitization. Although this process can be regulated by Ca 2+ -binding proteins such as calmodulin (CaM) and recoverin, the molecular mechanisms are poorly understood. Here, we report structural, computational, and biochemical analysis of a CaM complex with GRK5, revealing how CaM shapes GRK5 response to calcium. The CaM N and C domains bind independently to two helical regions at the GRK5 N and C termini to inhibit GPCR phosphorylation, though only the C domain interaction disrupts GRK5 membrane association, thereby facilitating cytoplasmic translocation. The CaM N domain strongly activates GRK5 via ordering of the amphipathic αN-helix of GRK5 and allosteric disruption of kinase-RH domain interaction for phosphorylation of cytoplasmic GRK5 substrates. These results provide a framework for understanding how two functional effects, GRK5 activation and localization, can cooperate under control of CaM for selective substrate targeting by GRK5.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
G protein-coupled receptor kinase 5591Homo sapiensMutation(s): 4 
Gene Names: GRK5GPRK5
EC: 2.7.11.16
UniProt & NIH Common Fund Data Resources
Find proteins for P34947 (Homo sapiens)
Explore P34947 
Go to UniProtKB:  P34947
PHAROS:  P34947
GTEx:  ENSG00000198873 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP34947
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Calmodulin148Podiceps cristatusMutation(s): 0 
Gene Names: N338_03747
UniProt
Find proteins for A0A094NJQ6 (Podiceps cristatus)
Explore A0A094NJQ6 
Go to UniProtKB:  A0A094NJQ6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A094NJQ6
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.875α = 90
b = 83.061β = 90
c = 137.521γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing

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 StatesR01HL142310
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States5R35GM122541
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States4R01GM044944

Revision History  (Full details and data files)

  • Version 1.0: 2020-12-09
    Type: Initial release
  • Version 1.1: 2020-12-30
    Changes: Database references
  • Version 1.2: 2021-02-03
    Changes: Database references
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Refinement description