Download MendeleyLigand channel in pharmacologically stabilized rhodopsin.
Mattle, D., Kuhn, B., Aebi, J., Bedoucha, M., Kekilli, D., Grozinger, N., Alker, A., Rudolph, M.G., Schmid, G., Schertler, G.F.X., Hennig, M., Standfuss, J., Dawson, R.J.P.(2018) Proc Natl Acad Sci U S A 115: 3640-3645
- PubMed: 29555765
- DOI: https://doi.org/10.1073/pnas.1718084115
- Primary Citation of Related Structures:
6FK6, 6FK7, 6FK8, 6FK9, 6FKA, 6FKB, 6FKC, 6FKD - PubMed 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 ? 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.
Organizational Affiliation:
Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
