Ligand channel in pharmacologically stabilized rhodopsin

• DOI: 10.1073/pnas.1718084115
• Publication Date: 2018-03-19T19:17:58Z
• Authors: Daniel Mattle; Bernd Kuhn; Johannes Aebi; Marc Bedoucha; Demet Kekilli; Nathalie Grozinger; Andre Alker; Markus G. Rudolph; Georg Schmid; Gebhard F. X. Sch...; Michael Hennig; Jörg Standfuss; Roger J. P. Dawson
• Keywords: Models, Molecular; 0301 basic medicine; 2. Zero hunger; Rhodopsin; structural biology; drug discovery; chemical biology; rare diseases; ophthalmology; Protein Conformation; Protein Stability; rare diseases; chemical biology; Biological Sciences; Ligands; Receptors, G-Protein-Coupled; drug discovery; 3. Good health; Mice; ophthalmology; 03 medical and health sciences; Pharmaceutical Preparations; Drug Design; Animals; Humans; structural biology; Cells, Cultured

Significance A substantial number of known genetic disorders have their origin in mutations that cause misfolding or dysfunction of G protein-coupled receptors (GPCRs). Pharmacological chaperones can rescue such mutant receptors from the endoplasmic reticulum by stabilizing protein conformations that support trafficking into the target membrane. Rhodopsin-mediated retinitis pigmentosa is a misfolding disease that might be targeted by PCs. Here we present a structure-based drug design approach to identify nonretinal compounds that bind and stabilize the receptor. Surprisingly, selected hits induce a previously unknown conformation of the seven-transmembrane helix bundle. Our study thus provides a remarkable example for compound class discovery and for the adaptability of GPCRs to chemically diverse ligands.