The dynamic conformational landscape of the protein methyltransferase SETD8
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 13, 2019
- Source ID
- 10.7554/elife.45403
Entities
People
- Anqi Ma
- Cheng Luo
- Fabio Pittella Silva
- Fanwang Meng
- Gil Blum
- Hao Hu
- Hua Zou
- Hualiang Jiang
- Jian Jin
- John D. Chodera
- Junyi Wang
- K. C. Wong
- Kaixian Chen
- Kun Qian
- Kyle A Beauchamp
- Minkui Luo
- Nicolas Babault
- Peter J. Brown
- Rafal Wiewiora
- Robert J Skene
- Shi Chen
- Shijie Fan
- Wenyu Yu
- Wolfram Tempel
- Yujun George Zheng
Organizations
- AbbVie
- Boehringer Ingelheim (United States)
- Canada Foundation for Innovation
- Chinese Academy of Sciences
- Cornell University
- Eshelman Institute for Innovation, University of North Carolina
- Genome Canada
- Icahn School of Medicine at Mount Sinai
- Innovative Medicines Initiative
- Janssen Pharmaceuticals
- Memorial Sloan Kettering Cancer Center
- Merck & Co.
- Ministry of Economic Development, Trade and Employment
- National Cancer Institute
- National Institute of General Medical Sciences
- National Natural Science Foundation of China
- National Science and Technology Major Project
- Novartis (Germany)
- Pfizer
- Shanghai Institute of Materia Medica
- Shanghai Municipal Science and Technology Commission
- São Paulo Research Foundation
- Takeda Pharmaceutical Company
- United States Department of Defense
- University of Chinese Academy of Sciences
- University of Georgia
- University of Toronto
- Wellcome Trust