The dynamic conformational landscape of the protein methyltransferase SETD8

Chen, Shi; Wiewiora, Rafal P.; Meng, Fanwang; Babault, Nicolas; Ma, Anqi; Yu, Wenyu; Qian, Kun; Hu, Hao; Zou, Hua; Wang, Junyi; Fan, Shijie; Blum, Gil; Pittella-Silva, Fabio; Beauchamp, Kyle A.; Tempel, Wolfram; Jiang, Hualiang; Chen, Kaixian; Skene, Robert J.; Zheng, Yujun George; Brown, Peter J.; Jin, Jian; Luo, Cheng; Chodera, John D.; Luo, Minkui

doi:10.7554/elife.45403

Title: The dynamic conformational landscape of the protein methyltransferase SETD8

Journal Article · Mon May 13 00:00:00 EDT 2019 · eLife

DOI:https://doi.org/10.7554/elife.45403· OSTI ID:1628904

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^[8]; Beauchamp, Kyle A. ^[10]; Tempel, Wolfram ^[5]; Jiang, Hualiang ^[9]; Chen, Kaixian ^[9];

^[7]; Zheng, Yujun George ^[6];

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Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York (United States); Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York(United States)
Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York (United States); Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York (United States)
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)
Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York (United States); Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York (United States); Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York (United States); Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York (United States)
Structural Genomics Consortium, University of Toronto, Toronto (Canada)
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens (United States)
Takeda California, Science Center Drive, San Diego (United States)
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York (United States)
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); University of Chinese Academy of Sciences, Beijing (China)
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York (United States)
Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York (United States); Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York (United States); Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York (United States)
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York (United States); Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institute of General Medical Sciences; National Cancer Institute (NCI); Starr Cancer Consortium; National Natural Science Foundation of China (NSFC); K. C. Wong Education Foundation; Science and Technology Commission of Shanghai Municipality; National Science & Technology Major Project of China; Chinese Academy of Sciences; Department of Defense (DOD); Canada Foundation for Innovation, Natural Sciences and Engineering Research Council of Canada; University of Saskatchewan; Government of Saskatchewan; Western Economic Diversification Canada; the National Research Council Canada; Canadian Institutes of Health Research

Grant/Contract Number:: AC02-06CH11357; R01GM096056, R01GM120570, 1R35GM131858; R01GM121505; R01GM122749; R01GM126154; 5P30 CA008748; 91853205, 81625022; 81430084; 2180102008; 18431907100; 19XD1404700; 2018ZX09711002; W81XWH-17-1-0412; 115766; GM103403; OD021527

OSTI ID:: 1628904

Journal Information:: eLife, Vol. 8; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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