Structures of rhodopsin in complex with G-protein-coupled receptor kinase 1

Qiuyan Chen, Manolo Plasencia, Zhuang Li, Somnath Mukherjee, Dhabaleswar Patra, Chun-Liang Chen, Thomas Klose, Xin-Qiu Yao, Anthony A. Kossiakoff, Leifu Chang, Philip C. Andrews and John J. G. Tesmer ()
Additional contact information
Qiuyan Chen: Purdue University
Manolo Plasencia: University of Michigan
Zhuang Li: Purdue University
Somnath Mukherjee: University of Chicago
Dhabaleswar Patra: Purdue University
Chun-Liang Chen: Purdue University
Thomas Klose: Purdue University
Xin-Qiu Yao: Georgia State University
Anthony A. Kossiakoff: University of Chicago
Leifu Chang: Purdue University
Philip C. Andrews: University of Michigan
John J. G. Tesmer: Purdue University

Nature, 2021, vol. 595, issue 7868, 600-605

Abstract: Abstract G-protein-coupled receptor (GPCR) kinases (GRKs) selectively phosphorylate activated GPCRs, thereby priming them for desensitization1. Although it is unclear how GRKs recognize these receptors2–4, a conserved region at the GRK N terminus is essential for this process5–8. Here we report a series of cryo-electron microscopy single-particle reconstructions of light-activated rhodopsin (Rho*) bound to rhodopsin kinase (GRK1), wherein the N terminus of GRK1 forms a helix that docks into the open cytoplasmic cleft of Rho*. The helix also packs against the GRK1 kinase domain and stabilizes it in an active configuration. The complex is further stabilized by electrostatic interactions between basic residues that are conserved in most GPCRs and acidic residues that are conserved in GRKs. We did not observe any density for the regulator of G-protein signalling homology domain of GRK1 or the C terminus of rhodopsin. Crosslinking with mass spectrometry analysis confirmed these results and revealed dynamic behaviour in receptor-bound GRK1 that would allow the phosphorylation of multiple sites in the receptor tail. We have identified GRK1 residues whose mutation augments kinase activity and crosslinking with Rho*, as well as residues that are involved in activation by acidic phospholipids. From these data, we present a general model for how a small family of protein kinases can recognize and be activated by hundreds of different GPCRs.

Date: 2021
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DOI: 10.1038/s41586-021-03721-x

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