Show simple item record

dc.contributor.author
Mattle, Daniel
dc.contributor.author
Kuhn, Bernd
dc.contributor.author
Aebi, Johannes D.
dc.contributor.author
Bedoucha, Marc
dc.contributor.author
Kekilli, Demet
dc.contributor.author
Grozinger, Nathalie
dc.contributor.author
Alker, Andre
dc.contributor.author
Rudolph, Markus G.
dc.contributor.author
Schmid, Georg
dc.contributor.author
Schertler, Gebhard F.X.
dc.contributor.author
Hennig, Michael
dc.contributor.author
Standfuss, Jörg
dc.contributor.author
Dawson, Roger J.P.
dc.date.accessioned
2018-04-13T09:23:32Z
dc.date.available
2018-04-13T04:32:52Z
dc.date.available
2018-04-13T09:23:32Z
dc.date.issued
2018-04-03
dc.identifier.issn
0027-8424
dc.identifier.issn
1091-6490
dc.identifier.other
10.1073/pnas.1718084115
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/257529
dc.identifier.doi
10.3929/ethz-b-000257529
dc.description.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.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
National Acad. of Sciences
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
structural biology
en_US
dc.subject
drug discovery
en_US
dc.subject
chemical biology
en_US
dc.subject
rare diseases
en_US
dc.subject
ophthalmology
en_US
dc.title
Ligand channel in pharmacologically stabilized rhodopsin
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
dc.date.published
2018-03-19
ethz.journal.title
Proceedings of the National Academy of Sciences of the United States of America
ethz.journal.volume
115
en_US
ethz.journal.issue
14
en_US
ethz.journal.abbreviated
Proc Natl Acad Sci U S A
ethz.pages.start
3640
en_US
ethz.pages.end
3645
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Washington, DC
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2018-04-13T04:33:05Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2018-04-13T09:23:35Z
ethz.rosetta.lastUpdated
2022-03-28T19:43:17Z
ethz.rosetta.versionExported
true
ethz.COinS
ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.atitle=Ligand%20channel%20in%20pharmacologically%20stabilized%20rhodopsin&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20of%20the%20United%20States%20of%20America&rft.date=2018-04-03&rft.volume=115&rft.issue=14&rft.spage=3640&rft.epage=3645&rft.issn=0027-8424&1091-6490&rft.au=Mattle,%20Daniel&Kuhn,%20Bernd&Aebi,%20Johannes%20D.&Bedoucha,%20Marc&Kekilli,%20Demet&rft.genre=article&rft_id=info:doi/10.1073/pnas.1718084115&
 Search print copy at ETH Library

Files in this item

Thumbnail

Publication type

Show simple item record