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Agonists for 13 trace amine-associated receptors provide insight into the molecular basis of odor selectivity

Academic Article
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Overview

related to degree

  • Wacker, Daniel, Ph.D. in Biology, Scripps Research 2009 - 2013

authors

  • Ferrero, D. M.
  • Wacker, Daniel
  • Roque, M. A.
  • Baldwin, M. W.
  • Stevens, Raymond
  • Liberles, S. D.

publication date

  • July 2012

journal

  • ACS Chemical Biology  Journal

abstract

  • Trace amine-associated receptors (TAARs) are vertebrate olfactory receptors. However, ligand recognition properties of TAARs remain poorly understood, as most are "orphan receptors" without known agonists. Here, we identify the first ligands for many rodent TAARs and classify these receptors into two subfamilies based on the phylogeny and binding preference for primary or tertiary amines. Some mouse and rat orthologs have similar response profiles, although independent Taar7 gene expansions led to highly related receptors with altered ligand specificities. Using chimeric TAAR7 receptors, we identified an odor contact site in transmembrane helix III that functions as a selectivity filter. Homology models based on the β(2) adrenergic receptor structure indicate spatial proximity of this site to the ligand. Gain-of-function mutations at this site created olfactory receptors with radically altered odor recognition properties. These studies provide new TAAR ligands, valuable tools for studying receptor function, and general insights into the molecular pharmacology of G protein-coupled receptors.

subject areas

  • Amines
  • Amino Acid Sequence
  • Animals
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Sequence Data
  • Odorants
  • Rats
  • Receptors, G-Protein-Coupled
  • Smell
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Identity

PubMed Central ID

  • PMC3401279

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb300111e

PubMed ID

  • 22545963
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Additional Document Info

start page

  • 1184

end page

  • 1189

volume

  • 7

issue

  • 7

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