Positive
allosteric modulators (PAMs) of metabotropic glutamate
receptor type 5 (mGluR5), a prototypical class C G protein-coupled
receptor (GPCR), have shown therapeutic potential for various neurological
disorders. Understanding the allosteric activation mechanism is essential
for the rational design of mGluR5 PAMs. We studied the
actions of positive and negative allosteric modulators within the
transmembrane domain of mGluR5, using enhance-sampling
all-atom molecular dynamics simulations. We found dual binding modes
of the PAM, associated with distinct shapes of the allosteric pocket.
The negative allosteric modulators, in contrast, showed only one binding
mode. The simulations revealed the mechanism by which the PAM activated
the receptor, in the absence of the orthosteric agonist (the so-called
allosteric agonism). The mechanism relied on dynamic communications
between amino-acid motifs that are highly conserved across class C
GPCRs. The findings may guide structure-based design and virtual screening
of allosteric modulators for mGluR5 as well as for other
class C GPCRs.