The dynamic conformational landscape of the protein methyltransferase SETD8 Journal Article
| Authors: | 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. |
| Article Title: | 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. © 2019, Chen et al. |
| Keywords: | enzymology; epigenetics; biochemistry; computational chemistry; posttranslational modification; chemical biology; human |
| Journal Title: | eLife |
| Volume: | 8 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2019-05-13 |
| Start Page: | e45403 |
| Language: | English |
| DOI: | 10.7554/eLife.45403 |
| PUBMED: | 31081496 |
| PROVIDER: | scopus |
| PMCID: | PMC6579520 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 August 2019 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work