Structure of a Class C GPCR metabotropic glutamate receptor
Figure: Artist's rendering of
metabotropic glutamate receptor 1 (courtesy of TSRI).
Ray Stevens group (The Scripps Research Institute) and collaborators
The group of Ray Stevens at The Scripps Research Institute
and collaborators at Vanderbilt University determined the structure of Class
C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator.
This important receptor is linked to learning, memory, anxiety, pain and
brain disorders and is a potential target for drugs against cancer, chronic
pain, schizophrenia, Parkinson's, Alzheimer's and autism. Glutamate
receptors are classified as ionotropic or metabotropic. Ionotropic glutamate
receptors (iGluRs) act rapidly to form an ionic pore when the
neurotransmitter glutamate is bound; metabotropic glutamate receptors
(mGluRs) are associated with a more prolonged stimulus and act via a
G-protein signaling cascade. This is the first mGluR structure and also the
first Class C GPCR structure. Class C GPCRs form dimers mediated by a large
N-terminal extracellular domain, which was not present in the crystallized
construct. Nevertheless the transmembrane domain crystallized as a dimer,
mediated in part by cholesterol. In contrast to other GPCRs, the entrance to
the allosteric binding site, which is considered ripe for targeting drugs
that modulate activity, is almost completely covered by loops. The
structural template will help to guide challenging pharmaceutical design to
reach this site.
Citation: Wu, H, Wang, C, Gregory, KJ, Han, GW, Cho, HP,
Xia, Y, Niswender, CM, Katrich, V, Meiler, J, Cherezov, V, Conn, PJ, Stevens,
RC. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to
an allosteric modulator, Science 344, 58-64 (2014).