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-Structure paper
タイトル | Structure and dynamics of differential ligand binding in the human ρ-type GABA receptor. |
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ジャーナル・号・ページ | Neuron, Vol. 111, Issue 21, Page 3450-33464.e5, Year 2023 |
掲載日 | 2023年11月1日 |
著者 | John Cowgill / Chen Fan / Nandan Haloi / Victor Tobiasson / Yuxuan Zhuang / Rebecca J Howard / Erik Lindahl / |
PubMed 要旨 | The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABARs). Pharmacological properties of ...The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABARs). Pharmacological properties of ρ-type GABARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human ρ1 GABAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels. |
リンク | Neuron / PubMed:37659407 |
手法 | EM (単粒子) |
解像度 | 2.2 - 3.36 Å |
構造データ | EMDB-17045, PDB-8op9: EMDB-17106, PDB-8oq6: EMDB-17107, PDB-8oq7: EMDB-17108, PDB-8oq8: EMDB-17110, PDB-8oqa: |
化合物 | ChemComp-ABU: ChemComp-NAG: ChemComp-HEX: ChemComp-CL: ChemComp-HOH: ChemComp-OCT: ChemComp-D10: ChemComp-7P9: ChemComp-VZA: ChemComp-D12: ChemComp-RI5: |
由来 |
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キーワード | MEMBRANE PROTEIN / GABAA receptor / rho1 |