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The dynamic conformational landscape of the protein methyltransferase SETD8

文献类型：期刊论文

作者Chen, Shi1,2; Wiewiora, Rafal P.1,3; Meng, Fanwang4; Babault, Nicolas5,6,7,8; Ma, Anqi5,6,7,8; Yu, Wenyu9; Qian, Kun10; Hu, Hao10; Zou, Hua11; Wang, Junyi2
刊名ELIFE
出版日期2019-05-13
卷号8页码:76
ISSN号2050-084X
DOI10.7554/eLife.45403
通讯作者Luo, Cheng(cluo@simm.ac.cn) ; Chodera, John D.(john.chodera@choderalab.org) ; Luo, Minkui(luom@mskcc.org)
英文摘要Elucidating the conformational heterogeneity of proteins is essential for understanding protein function and developing exogenous ligands. With the rapid development of experimental and computational methods, it is of great interest to integrate these approaches to illuminate the conformational landscapes of target proteins. SETD8 is a protein lysine methyltransferase (PKMT), which functions in vivo via the methylation of histone and nonhistone targets. Utilizing covalent inhibitors and depleting native ligands to trap hidden conformational states, we obtained diverse X-ray structures of SETD8. These structures were used to seed distributed atomistic molecular dynamics simulations that generated a total of six milliseconds of trajectory data. Markov state models, built via an automated machine learning approach and corroborated experimentally, reveal how slow conformational motions and conformational states are relevant to catalysis. These findings provide molecular insight on enzymatic catalysis and allosteric mechanisms of a PKMT via its detailed conformational landscape.
WOS关键词MARKOV STATE MODELS ; X-RAY-DIFFRACTION ; HISTONE H4 ; VARIATIONAL APPROACH ; STRUCTURAL BIOLOGY ; TRANSITION-STATE ; CELL-CYCLE ; CRYSTALLOGRAPHY ; METHYLATION ; ASSOCIATION
资助项目UNC Eshelman Institute for Innovation ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Ontario Ministry of Economic Development and Innovation ; Novartis Pharma ; National Institute of General Medical Sciences[R35GM131858] ; National Institute of General Medical Sciences[R01GM120570] ; National Institute of General Medical Sciences[R01GM126154] ; National Institute of General Medical Sciences[R01GM121505] ; National Institute of General Medical Sciences[R01GM122749] ; National Institute of General Medical Sciences[R01GM096056] ; Merck ; Janssen Pharmaceuticals ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[21820202008] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[91853205] ; National Science & Technology Major Project of China[2018ZX09711002] ; Mr. William H. Goodwin and Mrs. Alice Goodwin Commonwealth Foundation for Cancer Research ; Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center ; Tri-Institutional Therapeutics Discovery Institute ; National Cancer Institute[5P30 CA008748] ; Starr Cancer Consortium ; Memorial Sloan-Kettering Cancer Center Functional Genomics Initiative ; Sloan Kettering Institute ; Memorial Sloan-Kettering Cancer Center ; K. C. Wong Education Foundation ; Chinese Academy of Sciences[XDA12020353] ; Tri-Institutional PhD Program in Chemical Biology ; U.S. Department of Defense[W81XWH-17-1-0412] ; AbbVie ; Bayer Pharma AG ; Boehringer Ingelheim ; Genome Canada ; Innovative Medicines Initiative ; Pfizer ; Sao Paulo Research Foundation ; Takeda Pharmaceutical Company ; Wellcome Trust ; Canada Foundation for Innovation
WOS研究方向Life Sciences & Biomedicine - Other Topics
语种英语
出版者ELIFE SCIENCES PUBLICATIONS LTD
WOS记录号WOS:000471862900001
源URL[http://119.78.100.183/handle/2S10ELR8/289439]  
专题新药研究国家重点实验室
通讯作者Luo, Cheng; Chodera, John D.; Luo, Minkui
作者单位1.Mem Sloan Kettering Canc Ctr, Triinst PhD Program Chem Biol, 1275 York Ave, New York, NY 10021 USA
2.Mem Sloan Kettering Canc Ctr, Chem Biol Program, 1275 York Ave, New York, NY 10021 USA
3.Mem Sloan Kettering Canc Ctr, Computat & Syst Biol Program, 1275 York Ave, New York, NY 10021 USA
4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai, Peoples R China
5.Icahn Sch Med Mt Sinai, Mt Sinai Ctr Therapeut Discovery, New York, NY 10029 USA
6.Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA
7.Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA
8.Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA
9.Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada
10.Univ Georgia, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA
推荐引用方式
GB/T 7714		 Chen, Shi,Wiewiora, Rafal P.,Meng, Fanwang,et al. The dynamic conformational landscape of the protein methyltransferase SETD8[J]. ELIFE,2019,8:76.
APA Chen, Shi.,Wiewiora, Rafal P..,Meng, Fanwang.,Babault, Nicolas.,Ma, Anqi.,...&Luo, Minkui.(2019).The dynamic conformational landscape of the protein methyltransferase SETD8.ELIFE,8,76.
MLA Chen, Shi,et al."The dynamic conformational landscape of the protein methyltransferase SETD8".ELIFE 8(2019):76.

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来源：上海药物研究所

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