The dynamic conformational landscape of the protein methyltransferase SETD8

• Main Authors: Shi Chen, Rafal P Wiewiora, Fanwang Meng, Nicolas Babault, Anqi Ma, Wenyu Yu, Kun Qian, Hao Hu, Hua Zou, Junyi Wang, Shijie Fan, Gil Blum, Fabio Pittella-Silva, Kyle A Beauchamp, Wolfram Tempel, Hualiang Jiang, Kaixian Chen, Robert J Skene, Yujun George Zheng, Peter J Brown, Jian Jin, Cheng Luo, John D Chodera, Minkui Luo
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2019-05-01
• Series: eLife
• Subjects: epigenetics; posttranslational modification; enzymology; computational chemistry
• Online Access: https://elifesciences.org/articles/45403

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.