Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics

doi:10.1529/biophysj.108.129601

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	Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics
	Xu, Yechun2,3 ; Colletier, Jacques-Philippe 4,5; Weik, Martin 5; Jiang, Hualiang1,6 ; Moult, John 7; Silman, Israel 3; Sussman, Joel L.2
刊名	BIOPHYSICAL JOURNAL
	2008-09-01
卷号	95 期号:5 页码:2500-2511
ISSN号	0006-3495
DOI	10.1529/biophysj.108.129601
文献子类	Article
英文摘要	The high aromatic content of the deep and narrow active-site gorge of acetylcholinesterase (AChE) is a remarkable feature of this enzyme. Here, we analyze conformational flexibility of the side chains of the 14 conserved aromatic residues in the active-site gorge of Torpedo californica AChE based on the 47 three-dimensional crystal structures available for the native enzyme, and for its complexes and conjugates, and on a 20-ns molecular dynamics (MD) trajectory of the native enzyme. The degree of flexibility of these 14 aromatic side chains is diverse. Although the side-chain conformations of F330 and W279 are both very flexible, the side-chain conformations of F120, W233, W432, Y70, Y121, F288, F290 and F331 appear to be fixed. Residues located on, or adjacent to, the V-loop (C67-C94), namely W84, Y130, Y442, and Y334, display different flexibilities in the MD simulations and in the crystal structures. An important outcome of our study is that the majority of the side-chain conformations observed in the 47 Torpedo californica AChE crystal structures are faithfully reproduced by the MD simulation on the native enzyme. Thus, the protein can assume these conformations even in the absence of the ligand that permitted their experimental detection. These observations are pertinent to structure-based drug design.
WOS关键词	TORPEDO-CALIFORNICA ACETYLCHOLINESTERASE ; PARTICLE MESH EWALD ; PERIPHERAL SITE ; BACK-DOOR ; ALZHEIMERS-DISEASE ; CRYSTAL-STRUCTURES ; PRODUCT CLEARANCE ; DRUG DESIGN ; BINDING ; SIMULATION
WOS研究方向	Biophysics
语种	英语
出版者	BIOPHYSICAL SOC
WOS记录号	WOS:000258473900033
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272816]
专题	药物发现与设计中心
通讯作者	Sussman, Joel L.
作者单位	1.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China; 2.Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel; 3.Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel; 4.Univ Calif Los Angeles, Dept Energy, Inst Genom & Proteom, Los Angeles, CA 90095 USA; 5.Inst Biol Struct, Lab Mol Biophys, F-38027 Grenoble, France; 6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Discovery & Design, Shanghai 201203, Peoples R China; 7.NIST, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA
推荐引用方式 GB/T 7714	Xu, Yechun,Colletier, Jacques-Philippe,Weik, Martin,et al. Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics[J]. BIOPHYSICAL JOURNAL,2008,95(5):2500-2511.
APA	Xu, Yechun.,Colletier, Jacques-Philippe.,Weik, Martin.,Jiang, Hualiang.,Moult, John.,...&Sussman, Joel L..(2008).Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics.BIOPHYSICAL JOURNAL,95(5),2500-2511.
MLA	Xu, Yechun,et al."Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics".BIOPHYSICAL JOURNAL 95.5(2008):2500-2511.