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-Structure paper
Title | Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation. |
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Journal, issue, pages | Cell, Vol. 187, Issue 5, Page 1160-1176.e21, Year 2024 |
Publish date | Feb 29, 2024 |
![]() | Sean M Burke / Mariia Avstrikova / Colleen M Noviello / Nuriya Mukhtasimova / Jean-Pierre Changeux / Ganesh A Thakur / Steven M Sine / Marco Cecchini / Ryan E Hibbs / ![]() ![]() |
PubMed Abstract | The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological ...The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily. |
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Methods | EM (single particle) |
Resolution | 2.19 - 3.31 Å |
Structure data | EMDB-42526, PDB-8ut1: EMDB-42537, PDB-8utb: EMDB-42841, PDB-8uzj: EMDB-43012, PDB-8v80: EMDB-43015, PDB-8v82: EMDB-43025, PDB-8v86: EMDB-43030, PDB-8v88: EMDB-43031, PDB-8v89: EMDB-43032, PDB-8v8a: EMDB-43034, PDB-8v8c: EMDB-43035, PDB-8v8d: |
Chemicals | ![]() ChemComp-CA: ![]() ChemComp-NAG: ![]() ChemComp-POV: ![]() ChemComp-9Z9: ![]() ChemComp-EPJ: ![]() ChemComp-HOH: ![]()
ChemComp-XG3: ![]() ChemComp-IVM: ![]()
ChemComp-YLR: ![]() ChemComp-I34: ![]()
ChemComp-YLI: ![]() ChemComp-R16: |
Source |
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![]() | MEMBRANE PROTEIN / Ion channel / modulator / PAM / NICOTINIC RECEPTOR |