8V89

Alpha7-nicotinic acetylcholine receptor time resolved resting state


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.53 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural mechanisms of alpha 7 nicotinic receptor allosteric modulation and activation.

Burke, S.M.Avstrikova, M.Noviello, C.M.Mukhtasimova, N.Changeux, J.P.Thakur, G.A.Sine, S.M.Cecchini, M.Hibbs, R.E.

(2024) Cell 187: 1160-1176.e21

  • DOI: https://doi.org/10.1016/j.cell.2024.01.032
  • Primary Citation of Related Structures:  
    8UT1, 8UTB, 8UZJ, 8V80, 8V82, 8V86, 8V88, 8V89, 8V8A, 8V8C, 8V8D

  • 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 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.


  • Organizational Affiliation

    Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562
A, B, C, D, E
599Homo sapiensMutation(s): 0 
Gene Names: CHRNA7NACHRA7cybC
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P0ABE7 (Escherichia coli)
Explore P0ABE7 
Go to UniProtKB:  P0ABE7
Find proteins for P36544 (Homo sapiens)
Explore P36544 
Go to UniProtKB:  P36544
PHAROS:  P36544
GTEx:  ENSG00000175344 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP36544P0ABE7
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
F, G, H, I, J
F, G, H, I, J, K, L, M, N, O
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
POV
Query on POV

Download Ideal Coordinates CCD File 
BA [auth D],
FA [auth E],
S [auth A],
T [auth B],
X [auth C]
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
C42 H82 N O8 P
WTJKGGKOPKCXLL-PFDVCBLKSA-N
9Z9
Query on 9Z9

Download Ideal Coordinates CCD File 
AA [auth C],
EA [auth D],
IA [auth E],
R [auth A],
W [auth B]
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en
C34 H56 O5
CEEBZAXXSRFQIC-GZSGZGDASA-N
R16
Query on R16

Download Ideal Coordinates CCD File 
DA [auth D],
HA [auth E],
Q [auth A],
V [auth B],
Z [auth C]
HEXADECANE
C16 H34
DCAYPVUWAIABOU-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
CA [auth D],
GA [auth E],
P [auth A],
U [auth B],
Y [auth C]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.53 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)United StatesNS120496

Revision History  (Full details and data files)

  • Version 1.0: 2024-02-21
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Database references
  • Version 1.3: 2024-03-13
    Changes: Database references