Structural determinants of a conserved enantiomer-selective carvone binding pocket in the human odorant receptor OR1A1.
Level 5 - mechanism / opinion, no new human data
Bench and computational research using in silico modeling, mutagenesis, and in vitro cell-based assays.
PubMed 28656349 · doi:10.1007/s00018-017-2576-z
What was done
The authors used homology modeling accounting for odorant receptor (OR)-specific proline conformations, molecular docking, single-nucleotide polymorphism (SNP) analysis, and site-directed mutagenesis to examine carvone stereoisomer recognition. Functional receptor responses to (R)-(-)-carvone (spearmint) and (S)-(+)-carvone (caraway) were measured using recombinant human OR1A1 and murine Olfr43 in a cell-based, real-time luminescence assay. Findings were compared across orthologs from 36 mammalian species.
What was found
The analyses identified 11 amino acid positions that form an enantioselective binding pocket required for carvone function in human OR1A1 and mouse Olfr43. Ortholog comparison across 36 mammalian species demonstrated a hominid-specific carvone binding pocket with approximately 100% conservation. In addition, loss-of-function SNPs were identified within the carvone binding pocket of OR1A1. Specific numerical activation parameters and statistical effect sizes were not reported in the abstract.
Why it matters
The study identifies molecular determinants that allow human olfactory receptors to distinguish chiral odorants, providing a mechanistic candidate (OR1A1) and genetic variants to explain human (R)-(-)-carvone-specific anosmia.
Limits
This was strictly an in vitro and computational modeling study; no human sensory testing or in vivo validation was conducted. Quantitative functional data (such as EC50 values, fold-changes, or activation kinetics) are not reported in the abstract.
Cited by
- supports The flavoring agents of dill and spearmint are enantiomers of the same molecule, carvone, differing only in optical rotation (R-carvone and S-carvone).