9SLM

GABA-A a4b3d receptor in complex with GABA and Nb24

This is a non-PDB format compatible entry.

Summary for 9SLM

• Entry DOI: 10.2210/pdb9slm/pdb
• EMDB information: 55007
• Descriptor: Gamma-aminobutyric acid receptor subunit alpha-4,Gamma-aminobutyric acid type A receptor subunit alpha4, GAMMA-AMINO-BUTANOIC ACID, Gamma-aminobutyric acid receptor subunit beta-3, ... (11 entities in total)
• Functional Keywords: plgic, gaba, neurotransmission, extrasynaptic, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 266061.19

Authors

Nestorow, S.,Miller, P.S. (deposition date: 2025-09-04, release date: 2026-09-02, Last modification date: 2026-09-30)

Primary citation

Nestorow, S.A.,Chen, W.N.,Bertrand, D.,Wahid, A.A.,Wyatt, C.E.,Mortensen, M.,Clairfeuille, T.,Reutlinger, M.,Friz, G.,Pardon, E.,Steyaert, J.,Ladds, G.,Cecere, G.,Smart, T.G.,Hernandez, M.C.,Joedicke, L.,Miller, P.S.
Molecular arrangement and modulation of extrasynaptic alpha beta delta GABA A receptors.
Nat Commun, 17:-, 2026

PubMed Abstract: γ-aminobutyric acid Type-A (GABA) αβδ 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 δ-selective drug modulation remain unclear. We solve cryo-EM structures of α4β3δ receptors in an α-β-α-β-δ arrangement that contains two GABA binding pockets. GABA binding supports a classical β-subunit tilt and an outward configuration of the β-subunit M2-M3 loops. However, the δ 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 δ-selective positive allosteric modulator (PAM), DS2-Me, reveals binding to an α-δ 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 δ-selective modulation of these critical regulators of neuronal excitability.

PubMed: 42749722
DOI: 10.1038/s41467-026-76879-5

Experimental method

ELECTRON MICROSCOPY (3.27 Å)