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TitleStructural insights into the progressive recovery of α7 nicotinic acetylcholine receptor from nicotine-induced desensitization.
Journal, issue, pagesSci Adv, Vol. 11, Issue 41, Page eadx4432, Year 2025
Publish dateOct 10, 2025
AuthorsSanling Liu / Haopeng Chen / Xiaohong Zhu / Fei Ye / Yue Zhao / Junlin Qin / Yining Zheng / Xudong Wang / Longhua Zhang / Huan Chen / Xin Li / Wenjun Mu / Yaning Fu / Cheng Luo / Hongwei Hou / Chen Bai / Lei Liu / Changlin Tian /
PubMed AbstractNicotine is the predominant alkaloid in tobacco leaves and affects the human nervous system by interacting with nicotinic acetylcholine receptors (nAChRs). Chronic nicotine exposure leads to nAChR ...Nicotine is the predominant alkaloid in tobacco leaves and affects the human nervous system by interacting with nicotinic acetylcholine receptors (nAChRs). Chronic nicotine exposure leads to nAChR desensitization, while nicotine withdrawal leads to nAChR recovery. However, detailed molecular mechanisms underlying nicotine-induced nAChR desensitization and its recovery remain elusive. Here, we present cryo-EM structures of the α7 nAChR in complex with nicotine in both an open state and multiple desensitized states. Comparative analyses reveal progressive conformational changes during recovery from nicotine-induced desensitization and show that asymmetric nicotine binding disrupts the symmetry of the channel pore at the 16' and 17' sites. Integrating these findings with patch-clamp recordings and computational simulations, we identify an agonist-free structure that represents an atypical desensitized state closely resembling the resting conformation of α7 nAChR. These detailed mechanistic studies enhance our understanding of nicotine's effects on α7 nAChRs.
External linksSci Adv / PubMed:41071887 / PubMed Central
MethodsEM (single particle)
Resolution2.61 - 3.25 Å
Structure data

EMDB-63084, PDB-9lh5:
human alpha 7 nicotinic acetylcholine receptor in complex with L-nicotine (open state)
Method: EM (single particle) / Resolution: 2.61 Å

EMDB-63086, PDB-9lh6:
human alpha 7 nicotinic acetylcholine receptor in complex with L-nicotine (five-nicotine-bound desensitized state)
Method: EM (single particle) / Resolution: 2.69 Å

EMDB-63089, PDB-9lh8:
human alpha 7 nicotinic acetylcholine receptor in complex with L-nicotine (four-nicotine-bound desensitized state)
Method: EM (single particle) / Resolution: 2.74 Å

EMDB-63090, PDB-9lh9:
human alpha 7 nicotinic acetylcholine receptor in complex with L-nicotine (ortho-three-nicotine-bound desensitized state)
Method: EM (single particle) / Resolution: 2.98 Å

EMDB-63091, PDB-9lha:
human alpha 7 nicotinic acetylcholine receptor in complex with L-nicotine (meta-three-nicotine-bound desensitized state)
Method: EM (single particle) / Resolution: 2.96 Å

EMDB-63092, PDB-9lhb:
human alpha 7 nicotinic acetylcholine receptor in complex with L-nicotine (ortho-two-nicotine-bound desensitized state)
Method: EM (single particle) / Resolution: 3.11 Å

EMDB-63093, PDB-9lhc:
human alpha 7 nicotinic acetylcholine receptor in complex with L-nicotine (meta-two-nicotine-bound desensitized state)
Method: EM (single particle) / Resolution: 3.17 Å

EMDB-63094, PDB-9lhd:
human alpha 7 nicotinic acetylcholine receptor in complex with L-nicotine (one-nicotine-bound desensitized state)
Method: EM (single particle) / Resolution: 3.24 Å

EMDB-63095, PDB-9lhe:
human alpha 7 nicotinic acetylcholine receptor in complex with L-nicotine (nicotine-free desensitized state)
Method: EM (single particle) / Resolution: 3.25 Å

EMDB-65096, PDB-9viq:
human alpha 7 nicotinic acetylcholine receptor L277A mutant in complex with L-nicotine (desensitized state)
Method: EM (single particle) / Resolution: 3.24 Å

EMDB-65097, PDB-9vix:
human alpha 7 nicotinic acetylcholine receptor L278A mutant in complex with L-nicotine (desensitized state)
Method: EM (single particle) / Resolution: 3.06 Å

Chemicals

ChemComp-NCT:
(S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE

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

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Ligand-gated ion channel / Nicotine / Desensitization / Recovery / Open pore / Closed pore / mutant

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