Structural details of a Class B GPCR-arrestin complex revealed by genetically encoded crosslinkers in living cells

Yasmin Aydin, Thore Böttke, Jordy Homing Lam, Stefan Ernicke, Anna Fortmann, Maik Tretbar, Barbara Zarzycka, Vsevolod V. Gurevich, Vsevolod Katritch () and Irene Coin ()
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Yasmin Aydin: Leipzig University
Thore Böttke: Leipzig University
Jordy Homing Lam: University of Southern California
Stefan Ernicke: Leipzig University
Anna Fortmann: Leipzig University
Maik Tretbar: Leipzig University
Barbara Zarzycka: Vrije Universiteit Amsterdam
Vsevolod V. Gurevich: Vanderbilt University
Vsevolod Katritch: University of Southern California
Irene Coin: Leipzig University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Understanding the molecular basis of arrestin-mediated regulation of GPCRs is critical for deciphering signaling mechanisms and designing functional selectivity. However, structural studies of GPCR-arrestin complexes are hampered by their highly dynamic nature. Here, we dissect the interaction of arrestin-2 (arr2) with the secretin-like parathyroid hormone 1 receptor PTH1R using genetically encoded crosslinking amino acids in live cells. We identify 136 intermolecular proximity points that guide the construction of energy-optimized molecular models for the PTH1R-arr2 complex. Our data reveal flexible receptor elements missing in existing structures, including intracellular loop 3 and the proximal C-tail, and suggest a functional role of a hitherto overlooked positively charged region at the arrestin N-edge. Unbiased MD simulations highlight the stability and dynamic nature of the complex. Our integrative approach yields structural insights into protein-protein complexes in a biologically relevant live-cell environment and provides information inaccessible to classical structural methods, while also revealing the dynamics of the system.

Date: 2023
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DOI: 10.1038/s41467-023-36797-2

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