Structural insights into GABAA receptor potentiation by Quaalude
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Structural insights into GABAA receptor potentiation by Quaalude. / Chojnacka, Weronika; Teng, Jinfeng; Kim, Jeong Joo; Jensen, Anders A.; Hibbs, Ryan E.
In: Nature Communications, Vol. 15, No. 1, 5244, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structural insights into GABAA receptor potentiation by Quaalude
AU - Chojnacka, Weronika
AU - Teng, Jinfeng
AU - Kim, Jeong Joo
AU - Jensen, Anders A.
AU - Hibbs, Ryan E.
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - 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 GABAA 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 GABAA 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 GABAA receptor modulation through transmembrane binding sites.
AB - 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 GABAA 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 GABAA 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 GABAA receptor modulation through transmembrane binding sites.
U2 - 10.1038/s41467-024-49471-y
DO - 10.1038/s41467-024-49471-y
M3 - Journal article
C2 - 38898000
AN - SCOPUS:85196302106
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5244
ER -
ID: 395866867