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Structure paper

TitleDetermining the molecular and physiological actions of subtype-selective nanobodies of GABA receptors.
Journal, issue, pagesSci Adv, Vol. 12, Issue 31, Page eaeg3548, Year 2026
Publish dateJul 31, 2026
AuthorsJose Enrique Gonzalez-Prada / Sulin Liu / Chuhan Shang / Chloe S Chernoff / Damian P Bright / Martin Mortensen / Charlotte F Jones / Stephanie Nestorow / Vikram Babu Kasaragod / Wan-Na Chen / Saad Hannan / Jianchong Zhou / Alexander W E Dunn / Asma Soltani / Richard J Turner / Natasha M Duggan / Yin Yuan / Ayla A Wahid / Steven W Hardwick / Suzanne Scott / Dimitri Y Chirgadze / Els Pardon / Jan Steyaert / A Radu Aricescu / Ole Paulsen / David Belin / Trevor G Smart / Paul S Miller /
PubMed Abstractγ-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 ...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.
External linksSci Adv / PubMed:42525743 / PubMed Central
MethodsEM (single particle)
Resolution2.52 - 3.45 Å
Structure data

53206

9qjp

EMDB-53206, PDB-9qjp:
GABA-A receptor a3b3g2 + a3NB83(PAM) + GABA
Method: EM (single particle) / Resolution: 3.22 Å

53207

9qjq

EMDB-53207, PDB-9qjq:
GABA-A receptor a3b3 (1:4) + a3NB77(silent) + b3Mb125 + GABA
Method: EM (single particle) / Resolution: 2.63 Å

53208

9qjr

EMDB-53208, PDB-9qjr:
GABA-A receptor a2b3 (1:4) + a2NB29(near-silent) + b3Mb125 + GABA
Method: EM (single particle) / Resolution: 2.92 Å

53209

9qjs

EMDB-53209, PDB-9qjs:
GABA-A receptor a2b3 (1:4) + a2NB16(silent) + b3Mb125 + GABA
Method: EM (single particle) / Resolution: 2.52 Å

53212

9qjv

EMDB-53212, PDB-9qjv:
GABA-A receptor a2b3 (1:4) + a2NB47(silent) + b3Mb125 + GABA
Method: EM (single particle) / Resolution: 3.45 Å

53213

9qjx

EMDB-53213, PDB-9qjx:
GABA-A receptor a2b3g2 + a2NB00(PAM) + GABA
Method: EM (single particle) / Resolution: 2.7 Å

53214

9qjy

EMDB-53214, PDB-9qjy:
GABA-A receptor a2b3g2 + a2NB04(silent) + GABA
Method: EM (single particle) / Resolution: 2.78 Å

53215

9qk0

EMDB-53215, PDB-9qk0:
GABA-A receptor a2b3g2 + a2NB25(inhibitor)
Method: EM (single particle) / Resolution: 3.01 Å

53216

9qk1

EMDB-53216, PDB-9qk1:
GABA-A receptor a2b3 (1:4) + a2NB06(silent) + b3Mb125 + GABA
Method: EM (single particle) / Resolution: 3.05 Å

56081

9tnb

EMDB-56081, PDB-9tnb:
GABA-A receptor a3b3g2 + a3NB77 + bicuculline
Method: EM (single particle) / Resolution: 2.87 Å

56094

9tns

EMDB-56094, PDB-9tns:
GABA-A receptor a3b3g2 + GABA-PRE + a3NB83
Method: EM (single particle) / Resolution: 2.8 Å

56109

9tpq

EMDB-56109, PDB-9tpq:
GABA-A receptor a3b3g2 + a3NB77 + GABA
Method: EM (single particle) / Resolution: 2.94 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM

ChemComp-HSM:
HISTAMINE

ChemComp-HOH:
WATER

ChemComp-H0Z:
bicuculline methochloride

Source
  • homo sapiens (human)
  • lama glama (llama)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / pLGIC GABA Neurotransmission / pLGIC / GABA / Neurotransmission

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