8vqy
Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus methaqualone
Structural highlights
DiseaseGBRG2_HUMAN Childhood absence epilepsy;Dravet syndrome;Generalized epilepsy with febrile seizures-plus. Disease susceptibility is associated with variations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGBRG2_HUMAN Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.[1] Publication Abstract from PubMedMethaqualone, 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(A) 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(A) 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(A) receptor modulation through transmembrane binding sites. Structural insights into GABA(A) receptor potentiation by Quaalude.,Chojnacka W, Teng J, Kim JJ, Jensen AA, Hibbs RE Nat Commun. 2024 Jun 19;15(1):5244. doi: 10.1038/s41467-024-49471-y. PMID:38898000[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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