6wiv

Structure of human GABA(B) receptor in an inactive state

spinqualitylabelsall models 6wiv, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.3Å Ligands: CA, CLR, NAG, U3D, U3G Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The human GABAB receptor-a member of the class C family of G-protein-coupled receptors (GPCRs)-mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction(1). A unique GPCR that is known to require heterodimerization for function(2-6), the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands(7,8), while GABAB2 couples with G proteins(9-14). Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail(15). Although the VFT heterodimer structure has been resolved(16), the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor at atomic resolution, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique 'intersubunit latch' within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity. Structure of human GABAB receptor in an inactive state.,Park J, Fu Z, Frangaj A, Liu J, Mosyak L, Shen T, Slavkovich VN, Ray KM, Taura J, Cao B, Geng Y, Zuo H, Kou Y, Grassucci R, Chen S, Liu Z, Lin X, Williams JP, Rice WJ, Eng ET, Huang RK, Soni RK, Kloss B, Yu Z, Javitch JA, Hendrickson WA, Slesinger PA, Quick M, Graziano J, Yu H, Fiehn O, Clarke OB, Frank J, Fan QR Nature. 2020 Jun 24. pii: 10.1038/s41586-020-2452-0. doi:, 10.1038/s41586-020-2452-0. PMID:32581365 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also GABA receptor 3D structures

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