6fkc | pdb_00006fkc

Crystal structure of N2C/D282C stabilized opsin bound to RS15

spinqualitylabelsall models 6fkc, resolution 2.46Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6fkc is a 1 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.46Å Ligands: ACE, BMA, BOG, DLB, MAN, NAG, PLM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function OPSD_BOVIN Photoreceptor required for image-forming vision at low light intensity. Required for photoreceptor cell viability after birth. Light-induced isomerization of 11-cis to all-trans retinal triggers a conformational change leading to G-protein activation and release of all-trans retinal (By similarity). Publication Abstract from PubMed 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 A 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. Ligand channel in pharmacologically stabilized rhodopsin.,Mattle D, Kuhn B, Aebi J, Bedoucha M, Kekilli D, Grozinger N, Alker A, Rudolph MG, Schmid G, Schertler GFX, Hennig M, Standfuss J, Dawson RJP Proc Natl Acad Sci U S A. 2018 Mar 19. pii: 1718084115. doi:, 10.1073/pnas.1718084115. PMID:29555765 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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