6FKB

Crystal structure of N2C/D282C stabilized opsin bound to RS13

Summary for 6FKB

• Entry DOI: 10.2210/pdb6fkb/pdb
• Descriptor: Rhodopsin, PALMITIC ACID, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: rhodopsin, g protein-coupled receptors, retinitis pigmentosa, signaling protein, sensory transduction, photoreceptor protein, kintegral membrane protein, vision, membrane, receptor, transducer photoreceptor, small molecule complex, membrane protein
• Biological source: Bos taurus (Bovine)
• Cellular location: Membrane ; Multi- pass membrane protein : P02699
• Total number of polymer chains: 1
• Total formula weight: 40102.53

Authors

Mattle, D.,Standfuss, J.,Dawson, R. (deposition date: 2018-01-23, release date: 2018-04-04, Last modification date: 2024-01-17)

Primary citation

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.
Ligand channel in pharmacologically stabilized rhodopsin.
Proc. Natl. Acad. Sci. U.S.A., 115:3640-3645, 2018

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 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.

PubMed: 29555765
DOI: 10.1073/pnas.1718084115

Experimental method

X-RAY DIFFRACTION (3.03 Å)