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TitleStructural basis for allosteric agonism of human α7 nicotinic acetylcholine receptors.
Journal, issue, pagesCell Discov, Vol. 11, Issue 1, Page 35, Year 2025
Publish dateApr 8, 2025
AuthorsSanling Liu / Yining Zheng / Haopeng Chen / Xin Li / Qipeng Yan / Wenjun Mu / Yaning Fu / Huan Chen / Hongwei Hou / Lei Liu / Changlin Tian /
PubMed AbstractThe α7 nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel, plays important roles in cognition, neuroprotection, and anti-inflammation. As a potential drug target, α7 ...The α7 nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel, plays important roles in cognition, neuroprotection, and anti-inflammation. As a potential drug target, α7 nAChR has different binding sites for different ligands, particularly agonists and positive allosteric modulators (PAMs). Ago-PAMs can both directly activate and allosterically modulate α7 nAChR. However, the mechanism underlying α7 nAChR modulation by ago-PAM has yet to be fully elucidated. Here, we present cryo-EM structures of α7 nAChR in complex with the ago-PAM GAT107 and Ca in the open and desensitized states, respectively. Our results from both structural comparisons and functional assays suggest an allosteric mechanism underlying GAT107 modulation and calcium potentiation of α7 nAChR, involving local conformational changes in the ECD-TMD coupling region and a global structural rearrangement in the transmembrane domain. This work provides a new mechanism of α7 nAChR gating distinct from that of conventional agonist binding. These findings would aid in drug design and enrich our biophysical understanding of pentameric ligand-gated ion channels.
External linksCell Discov / PubMed:40195322 / PubMed Central
MethodsEM (single particle)
Resolution2.89 - 2.93 Å
Structure data

60604

9iir

EMDB-60604, PDB-9iir:
human alpha 7 nicotinic acetylcholine receptor in complex with GAT107 and calcium (desensitized state)
Method: EM (single particle) / Resolution: 2.93 Å

60606

9iiv

EMDB-60606, PDB-9iiv:
human alpha 7 nicotinic acetylcholine receptor in complex with GAT107 and calcium (open state)
Method: EM (single particle) / Resolution: 2.89 Å

Chemicals


ChemComp, No image

ChemComp-YLI:
Unknown entry

ChemComp-CA:
Unknown entry

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

ChemComp-CLR:
CHOLESTEROL

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Ligand-gated ion channel / Positive allosteric modulator / Ago-PAM / Allosteric modulation / Calcium potentiation

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