6PJX

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

Summary for 6PJX

• Entry DOI: 10.2210/pdb6pjx/pdb
• Related: 4TNB 4TND
• Descriptor: G protein-coupled receptor kinase 5, Calmodulin, SANGIVAMYCIN, ... (5 entities in total)
• Functional Keywords: g protein-coupled receptor (gpcr); g protein-coupled receptor kinase; phosphorylation; protein kinase; receptor regulation; signal transduction; calmodulin; calcium binding protein, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 85079.49

Authors

Bhardwaj, A.,Komolov, K.E.,Sulon, S.,Benovic, J.L. (deposition date: 2019-06-28, release date: 2020-12-09, Last modification date: 2024-11-06)

Primary citation

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.
Structure of a GRK5-Calmodulin Complex Reveals Molecular Mechanism of GRK Activation and Substrate Targeting.
Mol.Cell, 81:323-, 2021

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-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.

PubMed: 33321095
DOI: 10.1016/j.molcel.2020.11.026

Experimental method

X-RAY DIFFRACTION (1.96 Å)