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A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor

Publikation: Bidrag til tidsskriftTidsskriftartikel

  • Manuel Grundmann
  • Irina G Tikhonova
  • Brian D Hudson
  • Nicola J Smith
  • Klaus Mohr
  • Ulven, Trond
  • Graeme Milligan
  • Terry Kenakin
  • Evi Kostenis
Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand binding mode with transient activation of a first receptor site followed by sustained activation of a second topographically distinct site. We identify 4-CMTB (2-(4-chlorophenyl)-3-methyl-N-(thiazol-2-yl)butanamide), previously classified as a pure allosteric agonist of the free fatty acid receptor 2, as the first sequential activator and corroborate its two-step activation in living cells by tracking integrated responses with innovative label-free biosensors that visualize multiple signaling inputs in real time. We validate this unique pharmacology with traditional cellular readouts, including mutational and pharmacological perturbations along with computational methods, and propose a kinetic model applicable to the analysis of sequential receptor activation. We envision this form of dynamic agonism as a common principle of nature to spatiotemporally encode cellular information.
OriginalsprogEngelsk
TidsskriftCell Chemical Biology
Vol/bind23
Udgave nummer3
Sider (fra-til)392-403
Antal sider12
ISSN2451-9456
DOI
StatusUdgivet - 17 mar. 2016
Eksternt udgivetJa

ID: 189161795