Activation of metabotropic glutamate receptors
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Figure: Structures of inactive and active mGlu, where the CRD are shown in lime green. |
Brian Kobilka and George Skiniotis groups (Stanford University) and collaborators
The groups of Brian Kobilka, Georgios Skiniotis and
collaborators used a combination of crystallography and cryo-electron
microscopy to determine the inactive- and active-state structures of a
metabotropic glutamate receptor (mGlu). mGlus play important roles in
regulating neuronal responses to the neurotransmitter glutamate. The
mGlus belong to the Family C G protein coupled receptor (GPCRs), which
are distinguished from other GPCR families in that they are obligate
dimers that possess a large amino-terminal extracellular agonist
binding domain – the Venus flytrap (VFT) domain. The VFT domains are
linked to the G protein coupling transmembrane domains by cysteine rich
domains (CRD). Their structures show that agonist binding at the VFTs
leads to a compaction of the intersubunit dimer interface, thereby
bringing the CRDs into close proximity. Interactions between the CRDs
and the second extracellular loops of the receptor enable the rigid
body repositioning of the transmembran domains, which come into contact
with each other to initiate signaling. This structure was facilitated
by an allosteric nanobody that stabilized the VFT domain in the active
state.
Citation: Koehl, A, Hu, H, Feng, D, Sun, B, Zhang, Y,
Robertson, MJ, Chu, M, Kobilka, TS, Laeremans, T, Steyaert, J,
Tarrasch, J, Dutta, S, Fonseca, R, Weis, WI, Mathiesen, JM,
Skiniotis, G, Kobilka, BK, Structural insights into the
activation of metabotropic glutamate receptors, Nature
566, 79-84 (2019). DOI: 10.1038/s41586-019-0881-4
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