A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

doi:10.1073/pnas.0407739102

A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

^*Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093; ^†Department of Biosciences, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, CA 94550; and ^§School of Chemistry, Manchester University, Oxford Road, Manchester M139L, United Kingdom

Edited by Bruce J. Berne, Columbia University, New York, NY, and approved February 10, 2005 (received for review October 18, 2004)

Abstract

The nicotinic acetylcholine receptor is a well characterized ligandgated ion channel, yet a proper description of the mechanisms involved in gating, opening, closing, ligand binding, and desensitization does not exist. Until recently, atomic-resolution structural information on the protein was limited, but with the production of the x-ray crystal structure of the Lymnea stagnalis acetylcholine binding protein and the EM image of the transmembrane domain of the torpedo electric ray nicotinic channel, we were provided with a window to examine the mechanism by which this channel operates. A 15-ns all-atom simulation of a homology model of the homomeric human α7 form of the receptor was conducted in a solvated palmitoyl-2-oleoyl-sn-glycerol-phosphatidylcholine bilayer and examined in detail. The receptor was unliganded. The structure undergoes a twist-to-close motion that correlates movements of the C loop in the ligand binding domain, via the β10-strand that connects the two, with the 10° rotation and inward movement of two nonadjacent subunits. The Cys loop appears to act as a stator around which the α-helical transmembrane domain can pivot and rotate relative to the rigid β-sheet binding domain. The M2–M3 loop may have a role in controlling the extent or kinetics of these relative movements. All of this motion, along with essential dynamics analysis, is suggestive of the direction of larger motions involved in gating of the channel.

Footnotes

↵ ‡ To whom correspondence should be addressed. E-mail: rlaw{at}mccammon.ucsd.edu.
Author contributions: R.J.L. designed research; R.J.L. performed research; R.J.L. and R.H.H. contributed new reagents/analytic tools; R.J.L. analyzed data; and R.J.L. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: LGIC, ligand-gated ion channel; MD, molecular dynamics; LBD, ligand binding domain; TM, transmembrane; TMD, TM domain; AChBP, acetylcholine binding protein; hα7, human α7.