Barriers to ion translocation in cationic and anionic receptors from the Cys-loop family

被引:61
作者
Ivanov, Ivaylo
Cheng, Xiaolin
Sine, Steven M.
McCammon, J. Andrew
机构
[1] Univ Calif San Diego, Dept Chem & Biochem, Dept Pharmacol, Howard Hughes Med Inst, San Diego, CA 92103 USA
[2] Univ Calif San Diego, Ctr Theoret Biol Phys, San Diego, CA 92103 USA
[3] Mayo Clin, Coll Med, Dept Physiol & Biomed Engn, Rochester, MN 55905 USA
关键词
NICOTINIC ACETYLCHOLINE-RECEPTOR; MOLECULAR-DYNAMICS; GATING MECHANISM; TRANSMEMBRANE DOMAIN; CHANNEL; PORE; SELECTIVITY; MUTATIONS; WATER; GATE;
D O I
10.1021/ja070778l
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Understanding the mechanisms of gating and ion permeation in biological channels and receptors has been a long-standing challenge in biophysics. Recent advances in structural biology have revealed the architecture of a number of transmembrane channels and allowed detailed, molecular-level insight into these systems. Herein, we have examined the barriers to ion conductance and origins of ion selectivity in models of the cationic human alpha 7 nicotinic acetylcholine receptor (nAChR) and the anionic alpha 1 glycine receptor (GlyR), based on the structure of Torpedo nAChR. Molecular dynamics simulations were used to determine water density profiles along the channel length, and they established that both receptor pores were fully hydrated. The very low water density in the middle of the nAChR pore indicated the existence of a hydrophobic constriction. By contrast, the pore of GlyR was lined with hydrophilic residues and remained well-hydrated throughout. Adaptive biasing force simulations allowed us to reconstruct potentials of mean force (PMFs) for chloride and sodium ions in the two receptors. For the nicotinic receptor we observed barriers to ion translocation associated with rings of hydrophobic residues-Val13' and Leu9'-in the middle of the transmembrane domain. This finding further substantiates the hydrophobic gating hypothesis for nAChR. The PMF revealed no significant hydrophobic barrier for chloride translocation in GlyR. For both receptors nonpermeant ions displayed considerable barriers. Thus, the overall electrostatics and the presence of rings of charged residues at the entrance and exit of the channels were sufficient to explain the experimentally observed anion and cation selectivity.
引用
收藏
页码:8217 / 8224
页数:8
相关论文
共 35 条
[31]   Genomics, cys-loop ligand-gated ion channels and new targets for the control of insect pests and vectors [J].
Jones, Andrew K. .
CURRENT OPINION IN INSECT SCIENCE, 2018, 30 :1-7
[32]   The cys-loop ligand-gated ion channel gene superfamilies of the cockroaches Blattella germanica and Periplaneta americana [J].
Jones, Andrew K. ;
Goven, Delphine ;
Froger, Josy-Anne ;
Bantz, Alexandre ;
Raymond, Valerie .
PEST MANAGEMENT SCIENCE, 2021, 77 (08) :3787-3799
[33]   A mutational and molecular dynamics study of the cys-loop GABA receptor Hco-UNC-49 from Haemonchus contortus: Agonist recognition in the nematode GABA receptor family [J].
Foster, Josh ;
Cochrane, Everett ;
Khatami, Mohammad Hassan ;
Habibi, Sarah A. ;
de Haan, Hendrick ;
Forrester, Sean G. .
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, 2018, 8 (03) :534-539
[34]   secCl is a cys-loop ion channel necessary for the chloride conductance that mediates hormone-induced fluid secretion in Drosophila [J].
Feingold, Daniel ;
Knogler, Laura ;
Starc, Tanja ;
Drapeau, Pierre ;
O'Donnell, Michael J. ;
Nilson, Laura A. ;
Dent, Joseph A. .
SCIENTIFIC REPORTS, 2019, 9 (1)
[35]   The cys-loop ligand-gated ion channel gene superfamilies of the Lepidopteran species, Bombyx mori and Chilo suppressalis [J].
Jones, Andrew K. ;
Song, Zijiao ;
Huang, Qiutang ;
Mao, Xin ;
Jia, Zhongqiang ;
Jiang, Jie ;
Dandu, Tejeswini ;
Zhao, Chunqing .
INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2025, 182