PDBsum entry 6fkd

Membrane protein

PDB id: 6fkd

Contents

Protein chain

327 a.a.

Ligands

NAG-NAG-BMA-MAN-MAN

PLM

BOG ×5

DL2

Waters ×25

PDB id:

6fkd

Name:

Membrane protein

Title:

Crystal structure of n2c/d282c stabilized opsin bound to rs16

Structure:

Rhodopsin. Chain: a. Fragment: residues 1-326. Engineered: yes. Mutation: yes

Source:

Bos taurus. Bovine. Organism_taxid: 9913. Gene: rho. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293s gnti-.

Resolution:

2.49Å R-factor: 0.229 R-free: 0.250

Authors:

D.Mattle,J.Standfuss,R.Dawson

Key ref:

D.Mattle et al. (2018). Ligand channel in pharmacologically stabilized rhodopsin. Proc Natl Acad Sci U S A, 115, 3640-3645. PubMed id: 29555765 DOI: 10.1073/pnas.1718084115

Date:

23-Jan-18 Release date: 04-Apr-18

Protein chain

P02699  (OPSD_BOVIN) -  Rhodopsin from Bos taurus

Seq: 348 a.a.

Struc: 326 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1073/pnas.1718084115

Proc Natl Acad Sci U S A 115:3640-3645 (2018)

PubMed id: 29555765

Ligand channel in pharmacologically stabilized rhodopsin.

D.Mattle, B.Kuhn, J.Aebi, M.Bedoucha, D.Kekilli, N.Grozinger, A.Alker, M.G.Rudolph, G.Schmid, G.F.X.Schertler, M.Hennig, J.Standfuss, R.J.P.Dawson.

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.