Structural Basis for Activation of the Heterodimeric GABAB Receptor. Issue 22 (6th November 2020)

• Record Type: Journal Article
• Authors: Kim, Yoojoong; Jeong, Eunyoung; Jeong, Ji-Hong; Kim, Youngjin; Cho, Yunje
• Is Part Of: Journal of molecular biology. Volume 432:Issue 22(2020)
• Page Start: 5966
• Page End: 5984
• Publication Date: 2020-11-06
• Subjects: GABAB receptor -- class C GPCR -- conformational change -- signal transduction -- cryo-EM structure; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2020.09.023
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Structures of the GABAB receptor in inactive (light orange and light green) and active (orange and green) states are shown with Cryo-EM maps (gray) in the same orientation. Highlights: Cryo-EM structures for the inactive and active GABAB receptor were determined. TM domains interact through TM3 and TM5 in an open conformation in the inactive state. GABA binding reorients TM domains to form a TM5/6–TM6′/7′ interface in a closed conformation. PAM binding between TM6 and TM6 stabilizes the active TM domain conformation. The relayed structural rearrangement from VFTs to TMs via a linker and ECL2 may be conserved among all class C GPCRs. Abstract: The neurotransmitter γ-aminobutyric acid (GABA) activates the metabotropic GABAB receptor to generate slow, prolonged inhibitory signals that regulate the neural circuitry. The GABAB receptor is an obligate heterodimeric G protein-coupled receptor (GPCR) comprised of GBR1 and GBR2 subunits, each with extracellular, seven-helix transmembrane (7TM), and coiled-coil domains. To understand how GABA-driven conformational changes in the extracellular domain are transmitted to the 7TM domain during signal transduction, we determined cryo-electron microscopy (EM) structures of GABAB in two different states: an antagonist-bound inactive state, and an active state in which both the GABA agonist and a positive allosteric modulator (PAM) are bound. In the inactive state, the TM3 and TM5 helices in the two 7TM domains engage in cholesterol-mediated as well as direct interactions, resulting in an open conformation. GABA binding forces the extracellular domains of GBR1 and GBR2 into a compact form, relocating the linkers that connect the extracellular and 7TM domains closer to each other. The movement of the linker along with the associated extracellular loop 2 of the 7TM domain reorients the two 7TM domains and creates a new interface with the TM5, TM6 and TM7 helices in a closed conformation. PAM binding to the interface between the TM6 and TM6 helices stabilizes the active 7TM domain conformation. The relayed structural rearrangement results in significant conformational changes in the TM helices, as well as intracellular loop 3 in GBR2, which may promote the binding and activation of the Gi/o proteins.