Structures of metabotropic GABAB receptor
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Structures of metabotropic GABAB receptor. / Papasergi-Scott, Makaía M.; Robertson, Michael J.; Seven, Alpay B.; Panova, Ouliana; Mathiesen, Jesper M.; Skiniotis, Georgios.
In: Nature, Vol. 584, No. 7820, 2020, p. 310-314.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Structures of metabotropic GABAB receptor
AU - Papasergi-Scott, Makaía M.
AU - Robertson, Michael J.
AU - Seven, Alpay B.
AU - Panova, Ouliana
AU - Mathiesen, Jesper M.
AU - Skiniotis, Georgios
PY - 2020
Y1 - 2020
N2 - Stimulation of the metabotropic GABAB receptor by γ-aminobutyric acid (GABA) results in prolonged inhibition of neurotransmission, which is central to brain physiology1. GABAB belongs to family C of the G-protein-coupled receptors, which operate as dimers to transform synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins2,3. However, GABAB is unique in its function as an obligate heterodimer in which agonist binding and G-protein activation take place on distinct subunits4,5. Here we present cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABAB receptors. Complemented by cellular signalling assays and atomistic simulations, these structures reveal that extracellular loop 2 (ECL2) of GABAB has an essential role in relaying structural transitions by ordering the linker that connects the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of each of the subunits of GABAB caps and interacts with the hydrophilic head of a phospholipid that occupies the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G proteins. These results provide a starting framework through which to decipher the mechanistic modes of signal transduction mediated by GABAB dimers, and have important implications for rational drug design that targets these receptors.
AB - Stimulation of the metabotropic GABAB receptor by γ-aminobutyric acid (GABA) results in prolonged inhibition of neurotransmission, which is central to brain physiology1. GABAB belongs to family C of the G-protein-coupled receptors, which operate as dimers to transform synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins2,3. However, GABAB is unique in its function as an obligate heterodimer in which agonist binding and G-protein activation take place on distinct subunits4,5. Here we present cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABAB receptors. Complemented by cellular signalling assays and atomistic simulations, these structures reveal that extracellular loop 2 (ECL2) of GABAB has an essential role in relaying structural transitions by ordering the linker that connects the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of each of the subunits of GABAB caps and interacts with the hydrophilic head of a phospholipid that occupies the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G proteins. These results provide a starting framework through which to decipher the mechanistic modes of signal transduction mediated by GABAB dimers, and have important implications for rational drug design that targets these receptors.
U2 - 10.1038/s41586-020-2469-4
DO - 10.1038/s41586-020-2469-4
M3 - Journal article
C2 - 32580208
AN - SCOPUS:85086783636
VL - 584
SP - 310
EP - 314
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7820
ER -
ID: 247171435