Stepwise activation of a metabotropic glutamate receptor

Kaavya Krishna Kumar; Haoqing Wang; Chris Habrian; Naomi R Latorraca; Jun Xu; Evan S O'Brien; Chensong Zhang; Elizabeth Montabana; Antoine Koehl; Susan Marqusee; Ehud Y Isacoff; Brian K Kobilka

doi:10.1038/s41586-024-07327-x

Stepwise activation of a metabotropic glutamate receptor

Nature. 2024 Apr 17. doi: 10.1038/s41586-024-07327-x. Online ahead of print.

Authors

Kaavya Krishna Kumar^#¹, Haoqing Wang^#^{2

3}, Chris Habrian², Naomi R Latorraca⁴, Jun Xu², Evan S O'Brien², Chensong Zhang⁵, Elizabeth Montabana², Antoine Koehl^{2

6}, Susan Marqusee^{4

7

8}, Ehud Y Isacoff^{4

9}, Brian K Kobilka¹⁰

Affiliations

¹ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kaavyak@stanford.edu.
² Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
³ Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁴ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
⁵ Division of CryoEM and Bioimaging, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
⁶ Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA, USA.
⁷ QB3 Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
⁸ Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
⁹ Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
¹⁰ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kobilka@stanford.edu.

^# Contributed equally.

PMID: 38632403
DOI: 10.1038/s41586-024-07327-x

Abstract

Metabotropic glutamate receptors belong to a family of G protein-coupled receptors that are obligate dimers and possess a large extracellular ligand-binding domain that is linked via a cysteine-rich domain to their 7-transmembrane domain¹. Upon activation, these receptors undergo a large conformational change to transmit the ligand binding signal from the extracellular ligand-binding domain to the G protein-coupling 7-transmembrane domain². In this manuscript, we propose a model for a sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5. We present a series of structures in lipid nanodiscs, from inactive to fully active, including agonist-bound intermediate states. Further, using bulk and single-molecule fluorescence imaging, we reveal distinct receptor conformations upon allosteric modulator and G protein binding.