Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels

doi:10.1016/S0006-3495(02)75251-X

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 新药研究国家重点实验室

	Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels
	Fu, W ; Cui, M ; Briggs, JM ; Huang, XQ ; Xiong, B; Zhang, YM; Luo, XM; Shen, JH; Ji, RY ; Jiang, HL
刊名	BIOPHYSICAL JOURNAL
	2002-11
卷号	83 期号:5 页码:2370-2385
ISSN号	0006-3495
DOI	10.1016/S0006-3495(02)75251-X
文献子类	Article
英文摘要	The recognition of the scorpion toxin maurotoxin (MTX) by the voltage-gated potassium (Kv1) channels, Kv1.1, Kv1.2, and Kv1.3, has been studied by means of Brownian dynamics (BD) simulations. All of the 35 available structures of MTX in the Protein Data Bank (http://www.rcsb.org/pdb) determined by nuclear magnetic resonance were considered during the simulations, which indicated that the conformation of MTX significantly affected both the recognition and the binding between MTX and the Kv1 channels. Comparing the top five highest-frequency structures of MTX binding to the Kv1 channels, we found that the Kv1.2 channel, with the highest docking frequencies and the lowest electrostatic interaction energies, was the most favorable for MTX binding, whereas Kv1.1 was intermediate, and Kv1.3 was the least favorable one. Among the 35 structures of MTX, the 10th structure docked into the binding site of the Kv1.2 channel with the highest probability and the most favorable electrostatic interactions. From the MTX-Kv1.2 binding model, we identified the critical residues for the recognition of these two proteins through triplet contact analyses. MTX locates around the extracellular mouth of the Kv1 channels, making contacts with its beta-sheets. Lys23, a conserved amino acid in the scorpion toxins, protrudes into the pore of the Kv1.2 channel and forms two hydrogen bonds with the conserved residues Gly401 (D) and Tyr400(C) and one hydrophobic contact with Gly401 (C) of the Kv1.2 channel. The critical triplet contacts for recognition between MTX and the Kv1.2 channel are Lys23(MTX)-Asp402(C)(Kv1), Lys27(MTX)-Asp378(D)(Kv1), and Lys30(MTX)-Asp402(A)(Kv1). In addition, six hydrogen-bonding interactions are formed between residues Lys23, Lys27, Lys30, and Tyr32 of MTX and residues Gly401, Tyr400, Asp402, Asp378, and Thr406 of Kv1.2. Many of them are formed by side chains of residues of MTX and backbone atoms of the Kv1.2 channel. Five hydrophobic contacts exist between residues Pro20, Lys23, Lys30 and Tyr32 of MTX and residues Asp402, Val404, Gly401, and Arg377 of the Kv1.2 channel. The simulation results are in agreement with the previous molecular biology experiments and explain the binding phenomena between MTX and Kv1 channels at the molecular level. The consistency between the results of the BID simulations and the experimental data indicated that our three-dimensional model of the MTX-Kv1.2 channel complex is reasonable and can be used in additional biological studies, such as rational design of novel therapeutic agents blocking the voltage-gated channels and in mutagenesis studies in both the toxins and the Kv1 channels. In particular, both the BID simulations and the molecular mechanics refinements indicate that residue Asp378 of the Kv1.2 channel is critical for its recognition and binding functionality toward MTX. This phenomenon has not been appreciated in the previous mutagenesis experiments, indicating this might be a new clue for additional functional study of Kv1 channels.
WOS关键词	K+ CHANNELS ; HIGH-AFFINITY ; PROTEINS ; CHARYBDOTOXIN ; MUTATIONS ; MAURUS ; ASSOCIATION ; MECHANISMS ; INSIGHTS ; RECEPTOR
WOS研究方向	Biophysics
语种	英语
出版者	BIOPHYSICAL SOCIETY
WOS记录号	WOS:000179024500006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/274312]
专题	新药研究国家重点实验室中科院受体结构与功能重点实验室
通讯作者	Jiang, HL
作者单位	1.Chinese Acad Sci, Shanghai Inst Meteria Med, Ctr Drug Discovery & Design, State Key Lab Drug Res, Shanghai 200031, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China 3.Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA
推荐引用方式 GB/T 7714	Fu, W,Cui, M,Briggs, JM,et al. Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels[J]. BIOPHYSICAL JOURNAL,2002,83(5):2370-2385.
APA	Fu, W.,Cui, M.,Briggs, JM.,Huang, XQ.,Xiong, B.,...&Chen, KX.(2002).Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels.BIOPHYSICAL JOURNAL,83(5),2370-2385.
MLA	Fu, W,et al."Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels".BIOPHYSICAL JOURNAL 83.5(2002):2370-2385.