7c7s

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Cryo-EM structure of the CGP54626-bound human GABA(B) receptor in inactive state.

Structural highlights

7c7s is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.9Å
Ligands:2BV, NAG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GABR1_HUMAN Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Calcium is required for high affinity binding to GABA. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception. Activated by (-)-baclofen, cgp27492 and blocked by phaclofen.[1] [2] [3] [4] Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites.[5] [6] [7] [8]

Publication Abstract from PubMed

Metabotropic GABAB G protein-coupled receptor functions as a mandatory heterodimer of GB1 and GB2 subunits and mediates inhibitory neurotransmission in the central nervous system. Each subunit is composed of the extracellular Venus flytrap (VFT) domain and transmembrane (TM) domain. Here we present cryo-EM structures of full-length human heterodimeric GABAB receptor in the antagonist-bound inactive state and in the active state complexed with an agonist and a positive allosteric modulator in the presence of Gi1 protein at a resolution range of 2.8-3.0 A. Our structures reveal that agonist binding stabilizes the closure of GB1 VFT, which in turn triggers a rearrangement of TM interfaces between the two subunits from TM3-TM5/TM3-TM5 in the inactive state to TM6/TM6 in the active state and finally induces the opening of intracellular loop 3 and synergistic shifting of TM3, 4 and 5 helices in GB2 TM domain to accommodate the alpha5-helix of Gi1. We also observed that the positive allosteric modulator anchors at the dimeric interface of TM domains. These results provide a structural framework for understanding class C GPCR activation and a rational template for allosteric modulator design targeting the dimeric interface of GABAB receptor.

Cryo-EM structures of inactive and active GABAB receptor.,Mao C, Shen C, Li C, Shen DD, Xu C, Zhang S, Zhou R, Shen Q, Chen LN, Jiang Z, Liu J, Zhang Y Cell Res. 2020 Jun 3. pii: 10.1038/s41422-020-0350-5. doi:, 10.1038/s41422-020-0350-5. PMID:32494023[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
15 reviews cite this structure
Structural and Biophysical Mechanisms of Class C G Protein-Coupled Receptor Function.
Ellaithy et al. (2020)
14 more
29 other articles
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See Also

References

  1. ↑ Kaupmann K, Schuler V, Mosbacher J, Bischoff S, Bittiger H, Heid J, Froestl W, Leonhard S, Pfaff T, Karschin A, Bettler B. Human gamma-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K+ channels. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14991-6. PMID:9844003
  2. ↑ White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, Barnes AA, Emson P, Foord SM, Marshall FH. Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature. 1998 Dec 17;396(6712):679-82. PMID:9872316 doi:http://dx.doi.org/10.1038/25354
  3. ↑ Nomura R, Suzuki Y, Kakizuka A, Jingami H. Direct detection of the interaction between recombinant soluble extracellular regions in the heterodimeric metabotropic gamma-aminobutyric acid receptor. J Biol Chem. 2008 Feb 22;283(8):4665-73. doi: 10.1074/jbc.M705202200. Epub 2007, Dec 28. PMID:18165688 doi:http://dx.doi.org/10.1074/jbc.M705202200
  4. ↑ Geng Y, Xiong D, Mosyak L, Malito DL, Kniazeff J, Chen Y, Burmakina S, Quick M, Bush M, Javitch JA, Pin JP, Fan QR. Structure and functional interaction of the extracellular domain of human GABA(B) receptor GBR2. Nat Neurosci. 2012 Jun 3;15(7):970-8. doi: 10.1038/nn.3133. PMID:22660477 doi:10.1038/nn.3133
  5. ↑ Kaupmann K, Schuler V, Mosbacher J, Bischoff S, Bittiger H, Heid J, Froestl W, Leonhard S, Pfaff T, Karschin A, Bettler B. Human gamma-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K+ channels. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14991-6. PMID:9844003
  6. ↑ White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, Barnes AA, Emson P, Foord SM, Marshall FH. Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature. 1998 Dec 17;396(6712):679-82. PMID:9872316 doi:http://dx.doi.org/10.1038/25354
  7. ↑ Nomura R, Suzuki Y, Kakizuka A, Jingami H. Direct detection of the interaction between recombinant soluble extracellular regions in the heterodimeric metabotropic gamma-aminobutyric acid receptor. J Biol Chem. 2008 Feb 22;283(8):4665-73. doi: 10.1074/jbc.M705202200. Epub 2007, Dec 28. PMID:18165688 doi:http://dx.doi.org/10.1074/jbc.M705202200
  8. ↑ Geng Y, Xiong D, Mosyak L, Malito DL, Kniazeff J, Chen Y, Burmakina S, Quick M, Bush M, Javitch JA, Pin JP, Fan QR. Structure and functional interaction of the extracellular domain of human GABA(B) receptor GBR2. Nat Neurosci. 2012 Jun 3;15(7):970-8. doi: 10.1038/nn.3133. PMID:22660477 doi:10.1038/nn.3133
  9. ↑ Mao C, Shen C, Li C, Shen DD, Xu C, Zhang S, Zhou R, Shen Q, Chen LN, Jiang Z, Liu J, Zhang Y. Cryo-EM structures of inactive and active GABA(B) receptor. Cell Res. 2020 Jul;30(7):564-573. PMID:32494023 doi:10.1038/s41422-020-0350-5

Contents


PDB ID 7c7s

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