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Updated: Feb 13, 2026

A Rhodopsin Transport Assay by High-Content Imaging Analysis
12:11

A Rhodopsin Transport Assay by High-Content Imaging Analysis

Published on: January 16, 2019

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Ligand channel in pharmacologically stabilized rhodopsin

Daniel Mattle1,2, Bernd Kuhn1, Johannes Aebi1

  • 1Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.

Proceedings of the National Academy of Sciences of the United States of America
|March 21, 2018
PubMed

Insights

Researchers discovered small molecules that stabilize the rhodopsin protein, a key factor in retinitis pigmentosa (RP). This finding offers a new therapeutic strategy for treating this degenerative eye disease by improving protein folding and cell survival.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Ophthalmology

Background:

  • Retinitis pigmentosa (RP) is a degenerative eye disease caused by protein misfolding, affecting cell metabolism and photoreceptor survival.
  • Current therapeutic strategies for RP aim to stabilize mutant rhodopsin (a G protein-coupled receptor) using pharmacological chaperones (PC) to improve folding and trafficking.

Purpose of the Study:

  • To identify novel small molecules that stabilize rhodopsin mutants.
  • To elucidate the structural basis of rhodopsin stabilization by small molecules.

Main Methods:

  • Virtual screening and thermofluor screening were employed to discover stabilizing small molecules.
  • Crystal structure determination of stabilized opsin (using hit S-RS1) at 2.4 Å resolution.
  • Chemical modification of a lead compound (S-RS1) and subsequent structural analysis.

Main Results:

  • Discovery of nonretinal small molecules that stabilize rhodopsin.
  • Determination of the crystal structure revealing the binding motif of stabilizers at the orthosteric site.
  • Identification of novel conformational changes in rhodopsin, including an open channel facilitating ligand exchange.

Conclusions:

  • The identified small molecules represent a promising therapeutic approach for rhodopsin-related retinitis pigmentosa.
  • Understanding rhodopsin's conformational flexibility is crucial for developing effective treatments.
  • This work provides a foundation for drug intervention against RP by stabilizing rhodopsin.
Keywords:
chemical biologydrug discoveryophthalmologyrare diseasesstructural biology

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