The α7 nicotinic acetylcholine receptor: Molecular modelling, electrostatics, and energetics

Abstract

The structure of a homopentameric alpha7 nicotinic acetylcholine receptor is modelled by combining structural information from two sources: the X-ray structure of a water soluble acetylcholine binding protein from Lymnea stagnalis, and the electron microscopy derived structure of the transmembrane domain of the Torpedo nicotinic receptor. The alpha7 nicotinic receptor model is generated by simultaneously optimising: (i) chain connectivity, (ii) avoidance of stereochemically unfavourable contacts, and (iii) contact between the beta1-beta2 and M2-M3 loops that have been suggested to be involved in transmission of conformational change between the extracellular and transmembrane domains. A Gaussian network model was used to predict patterns of residue mobility in the alpha7 model. The results of these calculations suggested a flexibility gradient along the transmembrane domain, with the extracellular end of the domain more flexible that the intracellular end. Poisson-Boltzmann (PB) energy calculations and atomistic (molecular dynamics) simulations were used to estimate the free energy profile of a Na+ ion as a function of position along the axis of the pore-lining M2 helix bundle of the transmembrane domain. Both types of calculation suggested a significant energy barrier to exist in the centre of the (closed) pore, consistent with a "hydrophobic gating" model. Estimations of the PB energy profile as a function of ionic strength suggest a role of the extracellular domain in determining the cation selectivity of the alpha7 nicotinic receptor. These studies illustrate how molecular models of members of the nicotinic receptor superfamily of channels may be used to study structure-function relationships.

Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor

“…The authors reported an energy profile similar to ours (see Fig. 6 of [4]): the energy decreased as the ion entered the protein, then rose in the middle of the extracellular domain, and dropped to a global minimum near the junction of the extracellular and transmembrane domains. The interaction energy remained high throughout the transmembrane domain, as in our results.…”

“…First, the large extracellular domain carries the recognition sites for both the natural agonist GABA and the clinically important benzodiazepines [3,27,96]. Secondly, the transmembrane domain forms the ion channel and contains the channel gate [4], in addition to an intra-helical hydrophobic pocket that is important for the interaction of these receptors with intravenous and volatile anaesthetics [39]. Finally, the intracellular domain contains portals through which ions access www.elsevier.com/locate/JMGM Journal of Molecular Graphics and Modelling 26 (2007) [760][761][762][763][764][765][766][767][768][769][770][771][772][773][774] the cell cytoplasm.…”

A Role for Leu118 of Loop E in Agonist Binding to the α7 Nicotinic Acetylcholine Receptor

“…In view of the important structural homology and sequence similarity (24% identity), between the AChBP and the ligand binding domain of neuronal ␣7, homology modeling can offer a useful tool to investigate ligand binding. The structure of the chicken ␣7 homopentamer has been constructed based on both the X-ray structure of the L. stagnalis AChBP and the electron microscopy-derived structure of the transmembrane region of the T. marmorata nicotinic receptor (Amiri et al, 2005). Le Novère et al (2002) built a three-dimensional model of the N-terminal domain of a homopentameric chicken ␣7 nAChR based on AChBP, which was then used to analyze the docking of ACh, epibatidine, and nicotine (Le Novère et al, 2002).…”

Structural Analysis and Ion Translocation Mechanisms of the Muscle-Type Acetylcholine Receptor Channel

“…The muscle AChR models show a different shape and conformation of the channel gate if compared to previous studies based on human AChRs. Most of the previous studies (18)(19)(20)(21)(22)(23) have revealed the presence of a hydrophobic gate of Val and leu residues located in the mid-TM region, such ring representing the most constricted region of the whole channel.…”