Structural Superimposition

Abstact

gamma-aminobutyric acid Type-A (GABA(A)) alphabetadelta receptors regulate neuronal excitability and contribute to sleep, mood and motor coordination. However, the molecular arrangements of these receptors and the basis of GABA activation and delta-selective drug modulation remain unclear. We solve cryo-EM structures of alpha4beta3delta receptors in an alpha-beta-alpha-beta-delta arrangement that contains two GABA binding pockets. GABA binding supports a classical beta-subunit tilt and an outward configuration of the beta-subunit M2-M3 loops. However, the delta subunit M2-M3 loop is orientated inward and the 9' activation gate in the pore is closed, consistent with the low efficacy for these receptors. Addition of a delta-selective positive allosteric modulator (PAM), DS2-Me, reveals binding to an alpha-delta pocket that causes the 9' activation gate to open. In this work we provide key insights into the stoichiometry, arrangement and molecular modes of GABA activation and delta-selective modulation of these critical regulators of neuronal excitability.