Structural basis for the allosteric modulation of rhodopsin by nanobody binding to its extracellular domain

• DOI: 10.1038/s41467-023-40911-9
• Publication Date: 2023-08-25T17:03:00Z
• Authors: Arum Wu; David Salom; John D. Hong; Aleksander Tworak; Kohei Watanabe; Els Pardon; Jan Steyaert; Hideki Kandori; Kota Katayama; Philip D. Kiser; Krzysztof Palczewski
• Keywords: Allosteric modulator; Conformational change

Abstract Rhodopsin is a prototypical G protein-coupled receptor (GPCR) critical for vertebrate vision. Research on GPCR signaling states has been facilitated using llama-derived nanobodies (Nbs), some of which bind to the intracellular surface allosterically modulate receptor. Extracellularly binding allosteric have also investigated, but structural basis their activity not resolved date. Here, we report library Nbs that extracellular rhodopsin and thermodynamics its activation process. Crystal structures Nb2 in complex with native reveal mechanism modulation involving loop 2 glycans. suppresses Schiff base deprotonation hydrolysis prevents outward movement helices five six – universal event GPCRs. mitigates protein misfolding disease-associated mutant rhodopsin. Our data show power photoactivation potentially serve as therapeutic agents misfolding.