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Proc Natl Acad Sci U S A. 2018 Apr 3;115(14):3640-3645. doi: 10.1073/pnas.1718084115. Epub 2018 Mar 19.

Ligand channel in pharmacologically stabilized rhodopsin.

Author information

1
Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
2
Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
3
Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
4
Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland; joerg.standfuss@psi.ch roger.dawson@roche.com.
5
Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland; joerg.standfuss@psi.ch roger.dawson@roche.com.

Abstract

In the degenerative eye disease retinitis pigmentosa (RP), protein misfolding leads to fatal consequences for cell metabolism and rod and cone cell survival. To stop disease progression, a therapeutic approach focuses on stabilizing inherited protein mutants of the G protein-coupled receptor (GPCR) rhodopsin using pharmacological chaperones (PC) that improve receptor folding and trafficking. In this study, we discovered stabilizing nonretinal small molecules by virtual and thermofluor screening and determined the crystal structure of pharmacologically stabilized opsin at 2.4 Å resolution using one of the stabilizing hits (S-RS1). Chemical modification of S-RS1 and further structural analysis revealed the core binding motif of this class of rhodopsin stabilizers bound at the orthosteric binding site. Furthermore, previously unobserved conformational changes are visible at the intradiscal side of the seven-transmembrane helix bundle. A hallmark of this conformation is an open channel connecting the ligand binding site with the membrane and the intradiscal lumen of rod outer segments. Sufficient in size, the passage permits the exchange of hydrophobic ligands such as retinal. The results broaden our understanding of rhodopsin's conformational flexibility and enable therapeutic drug intervention against rhodopsin-related retinitis pigmentosa.

KEYWORDS:

chemical biology; drug discovery; ophthalmology; rare diseases; structural biology

PMID:
29555765
PMCID:
PMC5889642
DOI:
10.1073/pnas.1718084115
[Indexed for MEDLINE]
Free PMC Article

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