Structure of human GABAB receptor in an inactive state

Jinseo Park, Ziao Fu, Aurel Frangaj, Jonathan Liu, Lidia Mosyak, Tong Shen, Vesna N. Slavkovich, Kimberly M. Ray, Jaume Taura, Baohua Cao, Yong Geng, Hao Zuo, Yongjun Kou, Robert Grassucci, Shaoxia Chen, Zheng Liu, Xin Lin, Justin P. Williams, William J. Rice, Edward T. Eng, Rick K. Huang, Rajesh K. Soni, Brian Kloss, Zhiheng Yu, Jonathan A. Javitch, Wayne A. Hendrickson, Paul A. Slesinger, Matthias Quick, Joseph Graziano, Hongtao Yu, Oliver Fiehn, Oliver B. Clarke (), Joachim Frank () and Qing R. Fan ()
Additional contact information
Jinseo Park: Columbia University
Ziao Fu: Columbia University
Aurel Frangaj: Columbia University
Jonathan Liu: Columbia University
Lidia Mosyak: Columbia University
Tong Shen: University of California Davis
Vesna N. Slavkovich: Columbia University
Kimberly M. Ray: Columbia University
Jaume Taura: Icahn School of Medicine at Mount Sinai
Baohua Cao: Columbia University
Yong Geng: Columbia University
Hao Zuo: Columbia University
Yongjun Kou: Chinese Academy of Sciences
Robert Grassucci: Columbia University
Shaoxia Chen: MRC Laboratory of Molecular Biology
Zheng Liu: Columbia University
Xin Lin: Columbia University
Justin P. Williams: Columbia University
William J. Rice: New York Structural Biology Center
Edward T. Eng: New York Structural Biology Center
Rick K. Huang: Howard Hughes Medical Institute
Rajesh K. Soni: Columbia University
Brian Kloss: New York Structural Biology Center
Zhiheng Yu: Howard Hughes Medical Institute
Jonathan A. Javitch: Columbia University
Wayne A. Hendrickson: Columbia University
Paul A. Slesinger: Icahn School of Medicine at Mount Sinai
Matthias Quick: Columbia University
Joseph Graziano: Columbia University
Hongtao Yu: University of Texas Southwestern Medical Center
Oliver Fiehn: University of California Davis
Oliver B. Clarke: Columbia University
Joachim Frank: Columbia University
Qing R. Fan: Columbia University

Nature, 2020, vol. 584, issue 7820, 304-309

Abstract: Abstract 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 addiction1. A unique GPCR that is known to require heterodimerization for function2–6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9–14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, 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, 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.

Date: 2020
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DOI: 10.1038/s41586-020-2452-0

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