Enhanced meta-analysis of acetylcholine binding protein structures reveals conformational signatures of agonism in nicotinic receptors

source extracted confidence: high 2026-04-09
#amino-acid-sequence #animals #aplysia #carrier-proteins #crystallography-x-ray

Enhanced meta-analysis of acetylcholine binding protein structures reveals conformational signatures of agonism in nicotinic receptors

Stober et al., 2012 | Protein Sci | Meta Analysis

Citation

Stober Spencer T, Abrams Cameron F. Enhanced meta-analysis of acetylcholine binding protein structures reveals conformational signatures of agonism in nicotinic receptors. Protein Sci. 2012-Mar;21(3):307-17. doi:10.1002/pro.2016

Abstract

The soluble acetylcholine binding protein (AChBP) is the default structural proxy for pentameric ligand-gated ion channels (LGICs). Unfortunately, it is difficult to recognize conformational signatures of LGIC agonism and antagonism within the large set of AChBP crystal structures in both apo and ligand-bound states, primarily because AChBP conformations in this set are nearly superimposable (root mean square deviation < 1.5 Å). We have undertaken a systematic, alignment-free approach to elucidate conformational differences displayed by AChBP that cleanly differentiate apo/antagonist-bound from agonist-bound states. Our approach uses statistical inference based on both crystallographic states and conformations sampled during long molecular dynamics simulations to select important inter-C(α) distances and map their collective values onto functional states. We observe that binding of (nAChR) agonists to AChBP elicits clockwise rotation of the inner β-sheet with respect to the outer β-sheet, causing tilting of the cys-loop away from the five-fold axis, in a manner quite similar to that speculated for α-subunits of the heteromeric nAChR structure (Unwin, J Mol Biol 2005;346:967), making this motion potentially important in transmission of the gating signal to the transmembrane domain of a LGIC. The method is also successful at discriminating partial from full agonists and supports the hypothesis that a particularly controversial ligand, lobeline, is in fact an LGIC antagonist.

Key Findings

The method is also successful at discriminating partial from full agonists and supports the hypothesis that a particularly controversial ligand, lobeline, is in fact an LGIC antagonist.

Outcomes Measured

  • Requires manual extraction

Population

Field Value
Population See abstract
Sample Size See abstract
Age Range See abstract
Condition See abstract

MeSH Terms

  • Amino Acid Sequence
  • Animals
  • Aplysia
  • Carrier Proteins
  • Crystallography, X-Ray
  • Ligands
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Nicotinic Agonists
  • Protein Conformation
  • Receptors, Nicotinic
  • Sequence Alignment

Evidence Classification

  • Level: Meta Analysis
  • Publication Types: Journal Article, Meta-Analysis, Research Support, U.S. Gov't, Non-P.H.S.
  • Vertical: niacin

Provenance

Source extracted via PubMed E-utilities API on 2026-04-09