6BOZ

Structure of human SETD8 in complex with covalent inhibitor MS4138

6BOZ の概要

• エントリーDOI: 10.2210/pdb6boz/pdb
• 分子名称: N-lysine methyltransferase KMT5A, 1,2-ETHANEDIOL, N-(3-{[7-(2-aminoethoxy)-6-methoxy-2-(pyrrolidin-1-yl)quinazolin-4-yl]amino}propyl)prop-2-enamide, ... (4 entities in total)
• 機能のキーワード: protein-small molecule inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44387.83

構造登録者

Babault, N.,Anqi, M.,Jin, J. (登録日: 2017-11-21, 公開日: 2019-05-01, 最終更新日: 2024-11-13)

主引用文献

Chen, S.,Wiewiora, R.P.,Meng, F.,Babault, N.,Ma, A.,Yu, W.,Qian, K.,Hu, H.,Zou, H.,Wang, J.,Fan, S.,Blum, G.,Pittella-Silva, F.,Beauchamp, K.A.,Tempel, W.,Jiang, H.,Chen, K.,Skene, R.J.,Zheng, Y.G.,Brown, P.J.,Jin, J.,Luo, C.,Chodera, J.D.,Luo, M.
The dynamic conformational landscape of the protein methyltransferase SETD8.
Elife, 8:-, 2019

PubMed 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.

PubMed: 31081496
DOI: 10.7554/eLife.45403

実験手法

X-RAY DIFFRACTION (2.4 Å)