Olfactory Receptor Proteins - Bioelectronic Nose: Integration of Biotechnology and Nanotechnology - page 51

Full agonist

100

Cons tu ve ac vity of
receptor in absence of
ligand

Par al agonist

50

antagonist

0

Inverse agonist

-25

10 -9 10 -8 10 -7 10 -6 10 -5

[ligand]

Fig. 3.1 Pharmaceutical definitions of different ligand types: full agonists are ligands that have
the same biological activity as the endogenous ligand (100 % efficacy), partial agonists show inter-
mediate efficacy. Some receptors exhibit a constitutive (basal) activity even in absence of their
ligand. Inverse agonists are ligands that decrease this basal activity (negative efficacy). Biased
agonists are ligands that stimulate G-protein independent signaling pathways (e.g., the arrestin
pathway) while acting as either inverse or partial agonists of G-protein signaling pathways [ 76 ].
Antagonists do not modify the receptor basal activity but prevent agonists from binding and acti-
vating the receptor. Irreversible antagonists/agonists, as their name suggests, bind irreversibly to
the receptor (usually by being covalently tethered to it). Subtype-selective agonists/antagonists
are ligands that are able to discriminate between different receptor subtypes. For instance, JDTiC
(see Table 3.1 ) is an antagonist with a high affinity and subtype selectivity for the human κ-opioid
receptor but not for the δand μ-opioid receptors [ 77 ]

This panel of 3D structures of class R GPCRs is sufficiently large to allow us to
reasonably identify features and properties common to receptors of this class and
extrapolate these findings to receptors for which no 3D structure is available yet, in
particular, ORs.
GPCR 3D structure consists of an extracellular N-terminus of various length in
class R receptors, from a short peptide for ORs to a large extra-cellular folded do-
main for glycoprotein receptors, a bundle of seven transmembrane helices that are
connected by three extracellular loops (ECLs) and three intracellular loops (ICLs)
and a cytoplasmic C-terminus that often contains an eighth α-helix that lies against
the cytoplasmic face of the membrane. The 3D structure can be roughly divided into
two modules, one containing the binding pocket and devoted to ligand recognition,
and one dedicated to signal transduction by binding to the Gα protein [ 31 ]. As a
rule, residues of the outermost part show a tendency to be less conserved than those
of the innermost part. This is in particular true for ORs since their binding pocket
contains so-called “hypervariable” residues needed to accommodate the large spec-
trum of possible odorant molecules [ 32 ]. This is reflected by the larger structural
diversity of the first module with an average root-mean-square deviation (RMSD)
of 2.7 Å compared to the second module with an average RMSD of 1.5 Å [ 31 ].