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Structural mechanism of ligand activation in human GABAB receptor

Nature volume 504, pages 254–259 (2013)Cite this article

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Abstract

Human GABAB (γ-aminobutyric acid class B) receptor is a G-protein-coupled receptor central to inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of the subunits GBR1 and GBR2. Here we present the crystal structures of a heterodimeric complex between the extracellular domains of GBR1 and GBR2 in the apo, agonist-bound and antagonist-bound forms. The apo and antagonist-bound structures represent the resting state of the receptor; the agonist-bound complex corresponds to the active state. Both subunits adopt an open conformation at rest, and only GBR1 closes on agonist-induced receptor activation. The agonists and antagonists are anchored in the interdomain crevice of GBR1 by an overlapping set of residues. An antagonist confines GBR1 to the open conformation of the inactive state, whereas an agonist induces its domain closure for activation. Our data reveal a unique activation mechanism for GABAB receptor that involves the formation of a novel heterodimer interface between subunits.

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Figure 1: Crystal structures of the GBR1bVFT:GBR2VFT complex.
Figure 2: Agonist-induced conformational changes.
Figure 3: Heterodimer interface.
Figure 4: Ligand recognition by GBR1bVFT.
Figure 5: Constitutive activity of disulphide-tethered GBR1b:GBR2 heterodimer.

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Protein Data Bank

Data deposits

Atomic coordinates and diffraction data for the structures reported here are deposited in the RCSB Protein Data Bank under accession codes 4MQE, 4MQF, 4MR7, 4MR8, 4MR9, 4MRM, 4MS1, 4MS3 and 4MS4.

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Acknowledgements

We thank W. A. Hendrickson and R. Kass for advice and support; I. Berger for the gift of pFBDM vector; K. Rajashankar, K. Perry, S. Banerjee, F. Murphy, I. Kourinov and D. Neau for help with data collection; Y. Chen for technical assistance; and M. Evelyn for reading the manuscript. This work was supported by the American Heart Association grant SDG0835183N and the National Institute of Health grant R01GM088454 (both to Q.R.F.). Q.R.F. is an Irma Hirschl Career Scientist, Pew Scholar, McKnight Scholar and Schaefer Scholar.

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  1. Department of Pharmacology, Columbia University, New York, 10032, New York, USA

    Yong Geng, Martin Bush, Lidia Mosyak, Feng Wang & Qing R. Fan

  2. Department of Pathology & Cell Biology, Columbia University, New York, 10032, New York, USA

    Qing R. Fan

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  1. Yong Geng
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Q.R.F. initiated the study and designed the experiments; Y.G., Q.R.F., M.B., L.M. and F.W. performed experiments and analysed data; Q.R.F. and Y.G. wrote the paper.

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Correspondence to Qing R. Fan.

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Geng, Y., Bush, M., Mosyak, L. et al. Structural mechanism of ligand activation in human GABAB receptor. Nature 504, 254–259 (2013). https://doi.org/10.1038/nature12725

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