The dynamic conformational landscape of the protein methyltransferase SETD8

  1. Shi Chen
  2. Rafal P Wiewiora
  3. Fanwang Meng
  4. Nicolas Babault
  5. Anqi Ma
  6. Wenyu Yu
  7. Kun Qian
  8. Hao Hu
  9. Hua Zou
  10. Junyi Wang
  11. Shijie Fan
  12. Gil Blum
  13. Fabio Pittella-Silva
  14. Kyle A Beauchamp
  15. Wolfram Tempel
  16. Hualiang Jiang
  17. Kaixian Chen
  18. Robert J Skene
  19. Yujun George Zheng
  20. Peter J Brown
  21. Jian Jin
  22. Cheng Luo  Is a corresponding author
  23. John D Chodera  Is a corresponding author
  24. Minkui Luo  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. McMaster University, Canada
  3. Icahn School of Medicine at Mount Sinai, United States
  4. University of Toronto, Canada
  5. The University of Georgia, United States
  6. Takeda, United States
  7. Shanghai Institute of Materia Medica, China

Abstract

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.

Data availability

The molecular dynamics datasets generated and analyzed in this study are available via the Open Science Framework at https://osf.io/2h6p4.The code used for the generation and analysis of the molecular dynamics data is available via a Github repository at https://github.com/choderalab/SETD8-materials.PDB files: 6BOZ for BC-Inh1, 5W1Y for BC-Inh2, 4IJ8 for BC-SAM, and 5V2N for APO.

The following previously published data sets were used

Article and author information

Author details

  1. Shi Chen

    Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5860-2616
  2. Rafal P Wiewiora

    Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8961-7183
  3. Fanwang Meng

    Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2886-7012
  4. Nicolas Babault

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  5. Anqi Ma

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  6. Wenyu Yu

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  7. Kun Qian

    Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1132-2374
  8. Hao Hu

    Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, United States
    Competing interests
    No competing interests declared.
  9. Hua Zou

    Takeda, San Diego, United States
    Competing interests
    No competing interests declared.
  10. Junyi Wang

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  11. Shijie Fan

    Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Shanghai, China
    Competing interests
    No competing interests declared.
  12. Gil Blum

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  13. Fabio Pittella-Silva

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  14. Kyle A Beauchamp

    Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  15. Wolfram Tempel

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  16. Hualiang Jiang

    Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Shanghai, China
    Competing interests
    No competing interests declared.
  17. Kaixian Chen

    Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Shanghai, China
    Competing interests
    No competing interests declared.
  18. Robert J Skene

    Takeda, San Diego, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1482-6546
  19. Yujun George Zheng

    Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, United States
    Competing interests
    No competing interests declared.
  20. Peter J Brown

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  21. Jian Jin

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2387-3862
  22. Cheng Luo

    Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Shanghai, China
    For correspondence
    cluo@simm.ac.cn
    Competing interests
    No competing interests declared.
  23. John D Chodera

    Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    john.chodera@choderalab.org
    Competing interests
    John D Chodera, was a member of the Scientific Advisory Board for Schrödinger, LLC during part of this study.Is a current member of the Scientific Advisory Board of OpenEye Scientific SoftwareThe Chodera laboratory receives or has received funding from multiple sources, including the National Institutes of Health, the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, XtalPi, the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award, and the Sloan Kettering Institute. A complete funding history for the Chodera lab can be found at http://choderalab.org/funding.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0542-119X
  24. Minkui Luo

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    luom@mskcc.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7409-7034

Funding

National Cancer Institute

  • Jian Jin
  • John D Chodera
  • Minkui Luo

K. C. Wong Education Foundation

  • Cheng Luo

Chinese Academy of Sciences

  • Cheng Luo

National Natural Science Foundation of China

  • Cheng Luo

the Tri-Institutional PhD Program in Chemical Biology

  • Shi Chen
  • Rafal P Wiewiora

Peer Reviewed Cancer Research Program of the Department of Defense

  • Rafal P Wiewiora

AbbVie

  • Peter J Brown

Bayer Pharma AG

  • Peter J Brown

Boehringer Ingelheim

  • Peter J Brown

Eshelman Institute for Innovation

  • Peter J Brown

Genome Canada

  • Peter J Brown

National Institute of General Medical Sciences

  • Yujun George Zheng
  • Jian Jin
  • John D Chodera
  • Minkui Luo

Innovative Medicines Initiative

  • Peter J Brown

Canada Foundation for Innovation

  • Peter J Brown

Janssen

  • Peter J Brown

Merck & Co.

  • Peter J Brown

Novartis Pharma AG

  • Peter J Brown

Ontario Ministry of Economic Development and Innovation

  • Peter J Brown

Pfizer

  • Peter J Brown

São Paulo Research Foundation-FAPESP

  • Peter J Brown

Takeda

  • Hua Zou
  • Robert J Skene
  • Peter J Brown

the Wellcome Trust

  • Peter J Brown

Eunice Kennedy Shriver National Institute of Child Health and Human Development

  • Jian Jin

Starr Cancer Consortium

  • John D Chodera
  • Minkui Luo

MSKCC Functional Genomics Initiative

  • John D Chodera
  • Minkui Luo

The Sloan Kettering Institute

  • Kyle A Beauchamp
  • John D Chodera
  • Minkui Luo

Mr. William H. Goodwin and Mrs. Alice Goodwin Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center

  • Minkui Luo

Tri-Institutional Therapeutics Discovery Institute

  • Minkui Luo

Louis V. Gerstner Young Investigator Award

  • John D Chodera

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sarel Jacob Fleishman, Weizmann Institute of Science, Israel

Publication history

  1. Received: January 22, 2019
  2. Accepted: May 8, 2019
  3. Accepted Manuscript published: May 13, 2019 (version 1)
  4. Version of Record published: June 17, 2019 (version 2)

Copyright

© 2019, Chen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Shi Chen
  2. Rafal P Wiewiora
  3. Fanwang Meng
  4. Nicolas Babault
  5. Anqi Ma
  6. Wenyu Yu
  7. Kun Qian
  8. Hao Hu
  9. Hua Zou
  10. Junyi Wang
  11. Shijie Fan
  12. Gil Blum
  13. Fabio Pittella-Silva
  14. Kyle A Beauchamp
  15. Wolfram Tempel
  16. Hualiang Jiang
  17. Kaixian Chen
  18. Robert J Skene
  19. Yujun George Zheng
  20. Peter J Brown
  21. Jian Jin
  22. Cheng Luo
  23. John D Chodera
  24. Minkui Luo
(2019)
The dynamic conformational landscape of the protein methyltransferase SETD8
eLife 8:e45403.
https://doi.org/10.7554/eLife.45403

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