Biology Reference
In-Depth Information
A
B
K
A
/
a
OR
1
OR
1
A
R
1
O
A
K
O
K
O
/
a
γ
R
1
R
1
A
α
β
K
A
C
D
K
R2
/
a
OR
1
OR
1
R
2
R
1
R
2
O
K
O
K
O
/
a
γ
α
R
1
R
1
R
2
β
K
R2
FIGURE 9.1
The many faces of allosteric modulation of GPCRs. (A) Allosteric ligands of GPCRs (denoted
“A” on the scheme) can regulate orthosteric (O) ligand binding, the transmission of
ligand-induced conformational information to other parts of the receptor or the signaling
downstream of receptor activation. (B) The first representation of the allosteric ternary
complex model of drug action involves a GPCR, “R
1
” being bound by an orthosteric ligand
“O,” with an affinity constant, “
K
O
,” generating the “OR
1
” complex, leading to a cellular
stimulus downstream. Then, a third species, the allosteric ligand “A,” can bind the “R
1
O”
complex, with a specific affinity “
, which denotes the
magnitude and direction of the allosteric effect on ligand-binding affinity (
K
A
” and a binding cooperativity value of
a
a
¼
1, no effect,
negative allostery). (C) Dimeric receptor partners (as denoted “R
2
”
in the scheme) of GPCRs can also be considered as allosteric modulators, in the same way as
an allosteric ligand acts on a GPCR monomer or homodimer. (D) The allosteric ternary
complex model applied to a dimer partner.
1 positive allostery,
a>
a<
allosteric and orthosteric binding sites, a subclass of the so-called bitopic ligands
(
Valant, Sexton, & Christopoulos, 2009
). Bitopic ligands, in and of themselves,
are a very interesting class of molecules, which may combine a number of different
pharmacophores, comprising allosteric and orthosteric ligands on the same receptor
or between receptor equivalents in homo- and heterooligomeric GPCRs (
Kamal &
Jockers, 2009; Keov, Sexton, & Christopoulos, 2011
).
Allosteric modulation of class A GPCRs is thought to occur via regions outside
the heptahelical transmembrane domain, on the extracellular surface of the receptor,
which are less conserved and thus providing a basis for receptor-specific action
(
Peeters et al., 2011
). This type of modulation often stabilizes (or induces) specific
receptor conformations, altering coupling to distinct effector pathways. The first ex-
ample of such a regulator was identified for the neurokinin NK2 receptor. When
