8VRN

Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus PPTQ

これはPDB形式変換不可エントリーです。

8VRN の概要

• エントリーDOI: 10.2210/pdb8vrn/pdb
• EMDBエントリー: 43485
• 分子名称: Gamma-aminobutyric acid receptor subunit beta-2, 3-(4-methylphenyl)-2-phenylquinazolin-4(3H)-one, PHOSPHATIDYLETHANOLAMINE, ... (13 entities in total)
• 機能のキーワード: complex, pptq, drug modulation, gabaa receptor, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 372566.16

構造登録者

Chojnacka, W.,Teng, J.,Kim, J.J.,Jensen, A.A.,Hibbs, R.E. (登録日: 2024-01-22, 公開日: 2024-06-26, 最終更新日: 2025-05-28)

主引用文献

Chojnacka, W.,Teng, J.,Kim, J.J.,Jensen, A.A.,Hibbs, R.E.
Structural insights into GABA A receptor potentiation by Quaalude.
Nat Commun, 15:5244-5244, 2024

PubMed Abstract: Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABA receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABA receptor modulation through transmembrane binding sites.

PubMed: 38898000
DOI: 10.1038/s41467-024-49471-y

実験手法

ELECTRON MICROSCOPY (2.57 Å)