Two Gpcr Ligands Binding At Once Concept Of Allosterism

Despite sharing a common seven transmembrane (7TM)-spanning structure, GPCRs are malleable proteins that, as described in Section 2.3, have varying modes of endogenous ligand binding. In some cases, it appears that the endogenous, or orthosteric, binding pocket on one GPCR may represent a second, alternative, binding site on a different GPCR. This phenomenon has been observed for family C GPCRs where, in contrast to that for endogenous agonists, the binding pocket for a number of potent and selective synthetic ligands appears to reside exclusively within the heptahelical TM domains. Moreover, receptor mutagenesis studies have revealed that the location of this binding pocket correlates well with that for agonists and antagonists of rhodopsin-like GPCRs (Fig. 2.4) [45, 51, 62] . Any additional receptor binding sites that are topographically distinct from that of the orthosteric binding site are referred to as allosteric binding sites and the ligands that recognize them, allosteric modulators. GPCRs can be said to be natural allosteric proteins in that they require allosteric interactions to transmit stimulus from an extracellular agonist to an intracellular effector. However, in addition to intracellular proteins such as G proteins and P-arrestin, GPCRs can also be allosterically regulated by extracellular ions such as Zn2+, Na2+, and Ca2+, endogenous peptides, endogenous lipids, autoantibodies, and synthetic ligands (reviewed in Reference 63).

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