9TNS

GABA-A receptor a3b3g2 + GABA-PRE + a3NB83

This is a non-PDB format compatible entry.

Summary for 9TNS

• Entry DOI: 10.2210/pdb9tns/pdb
• EMDB information: 56094
• Descriptor: Gamma-aminobutyric acid receptor subunit alpha-3, GAMMA-AMINO-BUTANOIC ACID, GABA-A receptor beta-3-bril, ... (10 entities in total)
• Functional Keywords: plgic, gaba, neurotransmission, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 253829.64

Authors

Shang, C.,Nestorow, S.A.,Miller, P.S. (deposition date: 2025-12-16, release date: 2026-08-26)

Primary citation

Gonzalez-Prada, J.E.,Liu, S.,Shang, C.,Chernoff, C.S.,Bright, D.P.,Mortensen, M.,Jones, C.F.,Nestorow, S.,Kasaragod, V.B.,Chen, W.N.,Hannan, S.,Zhou, J.,Dunn, A.W.E.,Soltani, A.,Turner, R.J.,Duggan, N.M.,Yuan, Y.,Wahid, A.A.,Hardwick, S.W.,Scott, S.,Chirgadze, D.Y.,Pardon, E.,Steyaert, J.,Aricescu, A.R.,Paulsen, O.,Belin, D.,Smart, T.G.,Miller, P.S.
Determining the molecular and physiological actions of subtype-selective nanobodies of GABA A receptors.
Sci Adv, 12:eaeg3548-eaeg3548, 2026

PubMed Abstract: γ-Aminobutyric acid type-A (GABA) receptors are the principal mediators of inhibitory neurotransmission in the human central nervous system. The α- and α-containing subtypes have tightly controlled spatial expression profiles, which influence anxiety, nociception, epilepsy, and autism. α/α-Selective small molecules compromise on strength of effect (efficacy) to avoid off-subtype modulation. To break this pharmacological deadlock, we study here a panel of nanobodies (NBs) raised against α- and α-containing GABA receptors. We identify subtype selective silent binders, positive allosteric modulators (PAMs), and inhibitors. Cryo-electron microscopy structures explain the binding modes and molecular mechanisms of action of representative NBs. Modulators exhibit distinct synaptic and extrasynaptic functional profiles in brain slices and neuronal networks and can reduce anxiety in vivo. These selective and efficacious NBs (whether inhibitors or positive modulators) enable strong yet precise pharmacological control of α/α-containing subtypes to advance basic research and as potential therapeutic leads to treat neuropsychiatric disorders.

PubMed: 42525743
DOI: 10.1126/sciadv.aeg3548

Experimental method

ELECTRON MICROSCOPY (2.8 Å)