Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors

被引:104
作者
Cheng, Xiaolin [1 ]
Wang, Hailong
Grant, Barry
Sine, Steven M.
McCammon, J. Andrew
机构
[1] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, NSF, Ctr Theoret Biophys, Dept Chem & Biochem, La Jolla, CA 92093 USA
[3] Mayo Clin, Coll Med, Receptor Biol Lab, Dept Physiol & Biomed Engn, Rochester, MN USA
[4] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
关键词
D O I
10.1371/journal.pcbi.0020134
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
The initial coupling between ligand binding and channel gating in the human alpha 7 nicotinic acetylcholine receptor (nAChR) has been investigated with targeted molecular dynamics (TMD) simulation. During the simulation, eight residues at the tip of the C-loop in two alternating subunits were forced to move toward a ligand-bound conformation as captured in the crystallographic structure of acetylcholine binding protein (AChBP) in complex with carbamoylcholine. Comparison of apo- and ligand-bound AChBP structures shows only minor rearrangements distal from the ligand-binding site. In contrast, comparison of apo and TMD simulation structures of the nAChR reveals significant changes toward the bottom of the ligand-binding domain. These structural rearrangements are subsequently translated to the pore domain, leading to a partly open channel within 4 ns of TMD simulation. Furthermore, we confirmed that two highly conserved residue pairs, one located near the ligand-binding pocket (Lys145 and Tyr188), and the other located toward the bottom of the ligand-binding domain (Arg206 and Glu45), are likely to play important roles in coupling agonist binding to channel gating. Overall, our simulations suggest that gating movements of the a7 receptor may involve relatively small structural changes within the ligand-binding domain, implying that the gating transition is energy-efficient and can be easily modulated by agonist binding/unbinding.
引用
收藏
页码:1173 / 1184
页数:12
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