Abstract
Although pentameric ligand-gated ion channels (pLGICs) have been found to be the targets of general anesthetics, the mechanism of the effects of anesthetics on pLGICs remains elusive. pLGICs from Gloeobacter violaceus (GLIC) can be inhibited by the anesthetic ketamine. X-ray crystallography has shown that the ketamine binding site is distant from the channel gate of the GLIC. It is still not clear how ketamine controls the function of the GLIC by long-range allosteric regulation. In this work, the functionally crucial residues and allosteric pathway of anesthetic regulation of the GLIC were identified by use of a coarse-grained thermodynamic method developed by our group. In our method, the functionally crucial sites were identified as the residues thermodynamically coupled with binding of ketamine. The results from calculation were highly consistent with experimental data. Our study aids understanding of the mechanism of the anesthetic action of ketamine on the GLIC by long-range allosteric modulation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Atilgan AR, Durell SR, Jernigan RL, Demirel MC, Keskin O, Bahar I (2001) Anisotropy of fluctuation dynamics of proteins with an elastic network model. Biophys J 80:505–515
Atilgan C, Gerek ZN, Ozkan SB, Atilgan AR (2010) Manipulation of conformational change in proteins by single-residue perturbations. Biophys J 99:933–943
Baenziger JE, Corringer PJ (2011) 3D structure and allosteric modulation of the transmembrane domain of pentameric ligand-gated ion channels. Neuropharmacology 60:116–125
Bahar I, Rader AJ (2005) Coarse-grained normal mode analysis in structural biology. Curr Opin Struct Biol 15:586–592
Bahar I, Atilgan AR, Demirel MC, Erman B (1998) Vibrational dynamics of folded proteins significance of slow and fast motions in relation to function and stability. Phys Rev Lett 80:2733–2736
Bahar I, Lezon TR, Bakan A, Shrivastava IH (2010) Normal mode analysis of biomolecular structures functional mechanisms of membrane proteins. Chem Rev 110:1463–1497
Bocquet N, Nury H, Baaden M, Le Poupon C, Changeux JP, Delarue M, Corringer PJ (2009) X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457:111–114
Daily MD, Gray JJ (2009) Allosteric communication occurs via networks of tertiary and quaternary motions in proteins. PLoS Comput Biol 5:e1000293
Dror RO, Dirks RM, Grossman JP, Xu H, Shaw DE (2012) Biomolecular simulation: a computational microscope for molecular biology. Annu Rev Biophys 41:429–452
Du J, Dong H, Zhou HX (2012) Size matters in activation/inhibition of ligand-gated ion channels. Trends Pharmacol Sci 33:482–493
Dutta A, Bahar I (2010) Metal-binding sites are designed to achieve optimal mechanical and signaling properties. Structure 18:1140–1148
Franks NP (2008) General anaesthesiafrom molecular targetsto neuronal pathways of sleep and arousal. Nat Rev Neurosci 9:370–386
Friederich P, Dybek A, Urban BW (2000) Stereospecific interaction of ketamine with nicotinic acetylcholine receptors in human sympathetic ganglion-like SH-SY5Y cells. Anesthesiology 93:818–824
Grosman C, Zhou M, Auerbach A (2000) Mapping the conformational wave of acetylcholinereceptor channel gating. Nature 403:773–776
Grutter T, de Carvalho LP, Dufresne V, Taly A, Edelstein SJ, Changeux JP (2005) Molecular tuning of fast gating in pentameric ligand-gated ion channels. Proc Natl Acad Sci U S A 102:18207–18212
Gur M, Zomot E, Bahar I (2013) Global motions exhibited by proteins in micro- to milliseconds simulations concur with anisotropic network model predictions. J Chem Phys 139:121912
Haliloglu T, Bahar I, Erman B (1997) Gaussian dynamics of folded proteins. Phys Rev Lett 79:3090–3093
Haliloglu T, Gul A, Erman B (2010) Predicting important residues and interaction pathways in proteins using Gaussian Network Model: binding and stability of HLA proteins. PLoS Comput Biol 6:e1000845
Hilf RJ, Dutzler R (2009a) A prokaryotic perspective on pentameric ligand-gated ion channel structure. Curr Opin Struct Biol 19:418–424
Hilf RJ, Dutzler R (2009b) Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457:115–118
Hu XQ, Zhang L, Stewart RR, Weight FF (2003) Arginine 222 in the pre-transmembrane domain 1 of 5-HT3A receptors links agonist binding to channel gating. J Biol Chem 278:46583–46589
Isralewitz B, Gao M, Schulten K (2001) Steered molecular dynamics and mechanical functions of proteins. Curr Opin Struct Biol 11:224–230
Jha A, Cadugan DJ, Purohit P, Auerbach A (2007) Acetylcholine receptor gating at extracellular transmembrane domain interface: the cys-loop and M2–M3 linker. J Gen Physiol 130:547–558
Kar G, Keskin O, Gursoy A, Nussinov R (2010) Allostery and population shift in drug discovery. Curr Opin Pharmacol 10:715–722
Karplus M, McCammon JA (2002) Molecular dynamics simulation of biomolecules. Nature Struct Biol 9:646–652
Kash TL, Dizon MJ, Trudell JR, Harrison NL (2004) Charged residues in the beta2 subunit involved in GABAA receptor activation. J Biol Chem 279:4887–4893
Lee WY, Sine SM (2005) Principal pathway coupling agonist binding to channel gating in nicotinic receptors. Nature 438:243–247
Lee WY, Free CR, Sine SM (2009) Binding to gating transduction in nicotinic receptors: cys-loop energetically couples to pre-M1 and M2–M3 regions. J Neurosci 29:3189–3199
Lobo IA, Harris RA (2005) Sites of alcohol and volatile anaesthetic action on glycine receptors. Int Rev Neurobiol 65:53–87
Lynagh T, Lynch JW (2012) Molecular mechanisms of Cys loop ion channel receptor modulation by ivermectin. Front Mol Neurosci 5:60
Ma D, Kanada S (1997) Molecular switch in signal transduction Reaction paths of theconformational changes in ras p21. Proc Natl Acad Sci USA 94:11905–11910
Ming D, Wall ME (2005) Quantifying allosteric effects in proteins. Proteins 59:697–707
Mowrey D, Chen Q, Liang Y, Liang J, Xu Y, Tang P (2013) Signal transduction pathways in the pentameric ligand-gated ion channels. PLoS One 8:e64326
Nury H, Van Renterghem C, Weng Y, Tran A, Baaden M, Dufresne V, Changeux JP, Sonner JM, Delarue M, Corringer PJ (2011) X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469:428–431
Pan J, Chen Q, Willenbring D, Mowrey D, Kong XP, Cohen A, Divito CB, Xu Y, Tang P (2012a) Structure of the pentameric ligand-gated ion channel GLIC bound with anesthetic ketamine. Structure 20:1463–1469
Pan J, Chen Q, Willenbring D, Yoshida K, Tillman T, Kashlan OB, Cohen A, Kong XP, Xu Y, Tang P (2012b) Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine. Nat Commun 3:714
Purohit P, Auerbach A (2007) Acetylcholine receptor gating at extracellular transmembrane domain interface: the “pre-M1” linker. J Gen Physiol 130:559–568
Purohit P, Auerbach A (2013) Loop C and the mechanism of acetylcholine receptor-channel gating. J Gen Physiol 141:467–478
Ruvo MD, Giuliani A, Paci P, Santoni D, Di Paola L (2012) Shedding light on protein-ligand binding by graph theory: the topological nature of allostery. Biophys Chem 165–166:21–29
Saunders MG, Voth GA (2013) Coarse-graining methods for computational biology. Annu Rev Biophys 42:73–93
Solt K, Stevens RJ, Davies PA, Raines DE (2005) General anesthetic-induced channel gating enhancement of 5-hydroxytryptamine type 3 receptors depends on receptor subunit composition. The Journal of pharmacology and experimental therapeutics 315:771–776
Su JG, Xu XJ, Li CH, Chen WZ, Wang CX (2011) Identification of key residues for protein conformational transition using elastic network model. J Chem Phys 135:174101
Su JG, Du HJ, Hao R, Xu XJ, Li CH, Chen WZ, Wang CX (2013) Identification of functionally key residues in AMPA receptor with a thermodynamic method. J Phys Chem B 117:8689–8696
Tozzini V (2005) Coarse-grained models for proteins. Curr Opin Struct Biol 15:144–150
Tzeng SR, Kalodimos CG (2009) Dynamic activation of an allosteric regulatory protein. Nature 462:368–372
Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol 346:967–989
Xiu X, Hanek AP, Wang J, Lester HA, Dougherty DA (2005) A unified view of the role of electrostatic interactions in modulating the gating of Cys loop receptors. J Biol Chem 280:41655–41666
Zhang ZY, Shi YY, Liu HY (2003) Molecular dynamics simulations of peptides and proteins with amplified collective motions. Biophys J 84:3583–3893
Zheng W, Tekpinar M (2009) Large-scale evaluation of dynamically important residues in proteins predicted by the perturbation analysis of a coarse-grained elastic model. BMC Struct Biol 9:45
Zhu F, Hummer G (2009) Gating transition of pentameric ligand-gated ion channels. Biophys J 97:2456–2463
Zhu F, Hummer G (2010) Pore opening and closing of a pentameric ligand-gated ion channel. Proc Natl Acad Sci USA 107:19814–19819
Acknowledgments
This work was supported in part by grants from the National Natural Science Foundation of China (No. 11204267), the Natural Science Foundation of Hebei Province (A2014203126), and the Program for the Outstanding Young Talents of Hebei Province.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Xing Yuan Li and Fang Xie contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Li, X.Y., Xie, F., Zhang, J.C. et al. Study, by use of coarse-grained models, of the functionally crucial residues and allosteric pathway of anesthetic regulation of the Gloeobacter violaceus ligand-gated ion channel. Eur Biophys J 43, 623–630 (2014). https://doi.org/10.1007/s00249-014-0992-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00249-014-0992-7