Stepwise activation of a metabotropic glutamate receptor

• 成果类型: Article
• 署名作者: Kumar, Kaavya Krishna; Wang, Haoqing; Habrian, Chris; Latorraca, Naomi R.; Xu, Jun; O'Brien, Evan S.; Zhang, Chensong; Montabana, Elizabeth; Koehl, Antoine; Marqusee, Susan; Isacoff, Ehud Y.; Kobilka, Brian K.
• 署名单位: Stanford University; Stanford University; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6616
• DOI: 10.1038/s41586-024-07327-x
• 发表日期: 2024-05-23
• 关键词: particle cryo-em; software news; protein; binding; trajectories; fluorescence; modulators; DYNAMICS; STATES; mglu

摘要

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 domain(1). 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 domain(2). 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.