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Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations

文献类型：期刊论文

作者Xu, Yechun2,3,4; Li, Min-jun3; Greenblatt, Harry3; Chen, Wuyan2; Paz, Aviv3,4; Dym, Orly1,3; Peleg, Yoav1,3; Chen, Tiantian2; Shen, Xu2; He, Jianhua5
刊名ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
出版日期2012-01
卷号68页码:13-25
ISSN号0907-4449
DOI10.1107/S0907444911047251
文献子类Article
英文摘要beta-Secretase (beta-site amyloid precursor protein-cleaving enzyme 1; BACE1) is a transmembrane aspartic protease that cleaves the beta-amyloid precursor protein en route to generation of the amyloid beta-peptide (A beta) that is believed to be responsible for the Alzheimer's disease amyloid cascade. It is thus a prime target for the development of inhibitors which may serve as drugs in the treatment and/or prevention of Alzheimer's disease. In the following determination of the crystal structures of both apo and complexed BACE1, structural analysis of all crystal structures of BACE1 deposited in the PDB and molecular dynamics (MD) simulations of monomeric and 'dimeric' BACE1 were used to study conformational changes in the active-site region of the enzyme. It was observed that a flap able to cover the active site is the most flexible region, adopting multiple conformational states in the various crystal structures. Both the presence or absence of an inhibitor within the active site and the crystal packing are shown to influence the flap's conformation. An open conformation of the flap is mostly observed in the apo structures, while direct hydrogen-bonding interaction between main-chain atoms of the flap and the inhibitor is a prerequisite for the flap to adopt a closed conformation in the crystal structures of complexes. Thus, a systematic study of the conformational flexibility of the enzyme may not only contribute to structure-based drug design of BACE1 inhibitors and of other targets with flexible conformations, but may also help to better understand the mechanistic events associated with the binding of substrates and inhibitors to the enzyme.
WOS关键词STRUCTURE-BASED DESIGN ; HUMAN BETA-SECRETASE ; X-RAY-STRUCTURE ; AMYLOID PRECURSOR PROTEIN ; HYDROXY ETHYLAMINES HEAS ; FRAGMENT-BASED DISCOVERY ; CLEAVING ENZYME BACE ; INHIBITORS PART 2 ; ALZHEIMERS-DISEASE ; POTENT INHIBITORS
资助项目Shanghai Pujiang Program[10PJ1412000] ; National Natural Science Foundation of China[20720102040] ; State Key Program of Basic Research of China[2009CB918501] ; Israel Science Foundation[00000000] ; European Commission[031220] ; Teach-SG[ISSG-CT-2007-037198] ; Kimmelman Center for Biomolecular Structure and Assembly[00000000] ; Benoziyo Center for Neurosciences[00000000] ; Divadol Foundation[00000000] ; Nalvyco Foundation[00000000] ; Bruce Rosen Foundation[00000000] ; Lurman & Garoon Foundation[00000000] ; Computer Network Information Center (CNIC)[00000000] ; Chinese Academy of Sciences (CAS)[00000000] ; Shanghai Supercomputing Center (SCC)[00000000]
WOS研究方向Biochemistry & Molecular Biology ; Biophysics ; Crystallography
语种英语
WOS记录号WOS:000298412300002
出版者WILEY-BLACKWELL
源URL[http://119.78.100.183/handle/2S10ELR8/278288]  
专题药物发现与设计中心
通讯作者Xu, Yechun
作者单位1.Weizmann Inst Sci, Israel Struct Prote Ctr, IL-76100 Rehovot, Israel;
2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China;
3.Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel;
4.Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel;
5.Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai 201800, Peoples R China;
6.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Yechun,Li, Min-jun,Greenblatt, Harry,et al. Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations[J]. ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY,2012,68:13-25.
APA Xu, Yechun.,Li, Min-jun.,Greenblatt, Harry.,Chen, Wuyan.,Paz, Aviv.,...&Sussman, Joel L..(2012).Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations.ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY,68,13-25.
MLA Xu, Yechun,et al."Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations".ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY 68(2012):13-25.

入库方式： OAI收割

来源：上海药物研究所

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