Modeling of mammalian olfactory receptors and docking of odorants

Abstract

Olfactory receptors (ORs) belong to the superfamily of G protein-coupled receptors (GPCRs), the second largest class of genes after those related to immunity, and account for about 3 % of mammalian genomes. ORs are present in all multicellular organisms and represent more than half the GPCRs in mammalian species (e.g., the mouse OR repertoire contains >1,000 functional genes). ORs are mainly expressed in the olfactory epithelium where they detect odorant molecules, but they are also expressed in a number of other cells, such as sperm cells, although their functions in these cells remain mostly unknown. It has recently been reported that ORs are present in tumoral tissues where they are expressed at different levels than in healthy tissues. A specific OR is overexpressed in prostate cancer cells, and activation of this OR has been shown to inhibit the proliferation of these cells. Odorant stimulation of some of these receptors results in inhibition of cell proliferation. Even though their biological role has not yet been elucidated, these receptors might constitute new targets for diagnosis and therapeutics. It is important to understand the activation mechanism of these receptors at the molecular level, in particular to be able to predict which ligands are likely to activate a particular receptor ('deorphanization') or to design antagonists for a given receptor. In this review, we describe the in silico methodologies used to model the three-dimensional (3D) structure of ORs (in the more general framework of GPCR modeling) and to dock ligands into these 3D structures.

Discrimination between Olfactory Receptor Agonists and Non‐agonists

“…Other residues of our model were, however, not predicted to belong to the binding site (202, 259, 256, 260) emphasizing that atomic‐level models capture the ligand–receptor interface with a higher accuracy. Generally, our model is in line with available site‐directed mutagenesis on Ala112 residue 15. This amino acid is indeed located at the bottom of the binding pocket and its mutation affects odorant recognition.…”

G protein‐coupled odorant receptors: From sequence to structure

“…An alternative numbering scheme is proposed for the TM5 and TM6 of OR, which takes into account for highly conserved residues within these TMs (orange, italics). Site‐directed mutagenesis data are reported for the Human (h) OR1A1 and hOR1A2, 6 hOR1G1, hOR2AG1, Rat (r) and Mouse (m) I7, mOR‐EG, mOR42‐3, and mOR244‐3 . OR sequences are aligned with sequences of Bovine Rhodopsin (bRho), human β2‐adrenergic (hβ2AR), human Adenosine‐2A (hA2A), and human Chemokine‐1 (CXCR1) receptors.…”

Scents and sense: In silico perspectives on olfactory receptors

“…Nevertheless, the molecular basis of ligand binding and activation of ORs has been investigated by experimental methods and complemented by computational approaches. Sequence alignment of rhodopsin with OR sequences indicates that ORs have shorter TM regions and longer loops. In addition, the rhodopsin‐like GPCR subfamily (including ORs and the homology protein candidates opsins and catecholamine) display an average amino acid sequence similarity of 35–40% based on a set of OR sequences with varying lengths of 291–315 amino acids.…”

“… Sequence alignment of rhodopsin with OR sequences indicates that ORs have shorter TM regions and longer loops. In addition, the rhodopsin‐like GPCR subfamily (including ORs and the homology protein candidates opsins and catecholamine) display an average amino acid sequence similarity of 35–40% based on a set of OR sequences with varying lengths of 291–315 amino acids. Six conserved sequence patterns are found as important class A signature including GN, LHxPMYFFLxxLSxxD, MAYDRYVAICxPLxY, SY, KAFSTCxSH, and PxLNPxIYSLNR in TM1, TM2, TM3, TM5, TM6, and TM7, respectively.…”

“… Several residues located in TM1–7 and ECL2 are predicted to form the OR binding pocket based on sequencing, on modeling studies as well as on the few crystallized holoprotein GPCRs, that is, bound to an agonist. It has been suggested that the high flexibility of ORs to recognize and interact with many structurally different odor molecules is mainly due to the diverse side chains and backbone conformations of the residues in the binding pocket, which allow the pocket to adopt several different geometries. …”