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Cellular and Molecular Life Sciences

, Volume 74, Issue 22, pp 4209–4229 | Cite as

Structural determinants of a conserved enantiomer-selective carvone binding pocket in the human odorant receptor OR1A1

  • Christiane Geithe
  • Jonas Protze
  • Franziska Kreuchwig
  • Gerd Krause
  • Dietmar Krautwurst
Original Article

Abstract

Chirality is a common phenomenon within odorants. Most pairs of enantiomers show only moderate differences in odor quality. One example for enantiomers that are easily discriminated by their odor quality is the carvones: humans significantly distinguish between the spearmint-like (R)-(−)-carvone and caraway-like (S)-(+)-carvone enantiomers. Moreover, for the (R)-(−)-carvone, an anosmia is observed in about 8% of the population, suggesting enantioselective odorant receptors (ORs). With only about 15% de-orphaned human ORs, the lack of OR crystal structures, and few comprehensive studies combining in silico and experimental approaches to elucidate structure–function relations of ORs, knowledge on cognate odorant/OR interactions is still sparse. An adjusted homology modeling approach considering OR-specific proline-caused conformations, odorant docking studies, single-nucleotide polymorphism (SNP) analysis, site-directed mutagenesis, and subsequent functional studies with recombinant ORs in a cell-based, real-time luminescence assay revealed 11 amino acid positions to constitute an enantioselective binding pocket necessary for a carvone function in human OR1A1 and murine Olfr43, respectively. Here, we identified enantioselective molecular determinants in both ORs that discriminate between minty and caraway odor. Comparison with orthologs from 36 mammalian species demonstrated a hominid-specific carvone binding pocket with about 100% conservation. Moreover, we identified loss-of-function SNPs associated with the carvone binding pocket of OR1A1. Given carvone enantiomer-specific receptor activation patterns including OR1A1, our data suggest OR1A1 as a candidate receptor for constituting a carvone enantioselective phenotype, which may help to explain mechanisms underlying a (R)-(−)-carvone-specific anosmia in humans.

Keywords

Structure–function study Molecular modeling Site-directed mutagenesis GPCR Ortholog 

Abbreviations

AA

Amino acid

ECL

Extracellular loop

GPCR

G-protein coupled receptor

KFO

Key food odorant

OR

Odorant receptor

SNP

Single-nucleotide polymorphism

TMH

Transmembrane helix

Notes

Acknowledgements

We thank Matthias Kotthoff for the initial experiments, and Julia Fiedler for expert technical assistance.

Supplementary material

18_2017_2576_MOESM1_ESM.pdf (2.6 mb)
Supplementary material 1 (PDF 2677 kb)

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Deutsche Forschungsanstalt für Lebensmittelchemie Leibniz Institut (DFA)FreisingGermany
  2. 2.Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)BerlinGermany
  3. 3.Max-Delbrück-Centrum für Molekulare Medizin (MDC)BerlinGermany

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