dc.contributor.author
Bock, Andreas
dc.contributor.author
Bermudez, Marcel
dc.date.accessioned
2021-05-03T07:51:28Z
dc.date.available
2021-05-03T07:51:28Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/30244
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-29985
dc.description.abstract
G protein-coupled receptors (GPCRs) are essential cell membrane signaling molecules and represent the most important class of drug targets. Some signaling pathways downstream of a GPCR may be responsible for drug adverse effects, while others mediate therapeutic efficacy. Biased ligands preferentially activate only a subset of all GPCR signaling pathways. They hold great potential to become next-generation GPCR drugs with less side effects due to their potential to exclusively activate desired signaling pathways. However, the molecular basis of biased agonism is poorly understood. GPCR activation occurs through allosteric coupling, the propagation of conformational changes from the extracellular ligand-binding pocket to the intracellular G protein-binding interface. Comparison of GPCR structures in complex with G proteins or beta-arrestin reveals that intracellular transducer coupling results in closure of the ligand-binding pocket trapping the agonist inside its binding site. Allosteric coupling appears to be transducer-specific offering the possibility of harnessing this mechanism for the design of biased ligands. Here, we review the biochemical, pharmacological, structural, and biophysical evidence for allosteric coupling and delineate that biased agonism should be a consequence of preferential allosteric coupling from the ligand-binding pocket to one transducer-binding site. As transducer binding leads to large structural rearrangements in the extracellular ligand-binding pocket, we survey biased ligands with an extended binding mode that interact with extracellular receptor domains. We propose that biased ligands use ligand-specific triggers inside the binding pocket that are relayed through preferential allosteric coupling to a specific transducer, eventually leading to biased signaling.
en
dc.format.extent
16 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
allosteric coupling
en
dc.subject
biased agonism
en
dc.subject
biased ligands
en
dc.subject
drug discovery
en
dc.subject
G protein‐coupled receptors
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::570 Biowissenschaften; Biologie
dc.title
Allosteric coupling and biased agonism in G protein‐coupled receptors
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1111/febs.15783
dcterms.bibliographicCitation.journaltitle
FEBS Journal
dcterms.bibliographicCitation.number
8
dcterms.bibliographicCitation.pagestart
2513
dcterms.bibliographicCitation.pageend
2528
dcterms.bibliographicCitation.volume
288
dcterms.bibliographicCitation.url
https://doi.org/10.1111/febs.15783
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Pharmazie
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refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1742-4658
refubium.resourceType.provider
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