The molecular basis of drug selectivity for α5 subunit-containing GABAA receptors

Abstract

Abstractα5 subunit-containing γ-aminobutyric acid type A (GABAA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the β-carboline, methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an ‘upper’ and ‘lower’ moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct modulator binding modes and their basis of α5-subtype selectivity, appreciate structure–activity relationships, and empower future structure-based drug design campaigns.

Chemical Driving the Subtype Selectivity of Phytohormone Receptors Is Beneficial for Crop Productivity

“…This entails treating each receptor subtype as an independent entity before considering its functional redundancy. Pharmacological studies have provided a strategy called subtype selectivity as a means of navigating this complexity . A low-selectivity antagonist can interfere with the function of an entire protein family, while a selective agonist can specifically target one member of a group of redundant receptors such as pyrabactin (PYB), which serves as a selective agonist for ABA receptors.…”

“…Pharmacological studies have provided a strategy called subtype selectivity as a means of navigating this complexity. 12 A low-selectivity antagonist can interfere with the function of an entire protein family, while a selective agonist can specifically target one member of a group of redundant receptors such as pyrabactin (PYB), which serves as a selective agonist for ABA receptors. PYB presents a strategy distinct from knockouts, as it amplifies the function of PYR1 and leads to a significant phenotype.…”