Substrate-differentiated transition states of SET7/9-catalyzed lysine methylation Journal Article
| Authors: | Chen, S.; Kapilashrami, K.; Senevirathne, C.; Wang, Z.; Wang, J.; Linscott, J. A.; Luo, M. |
| Article Title: | Substrate-differentiated transition states of SET7/9-catalyzed lysine methylation |
| Abstract: | Transition state stabilization is essential for rate acceleration of enzymatic reactions. Despite extensive studies on various transition state structures of enzymes, an intriguing puzzle is whether an enzyme can accommodate multiple transition states (TSs) to catalyze a chemical reaction. It is experimentally challenging to study this proposition in terms of the choices of suitable enzymes and the feasibility to distinguish multiple TSs. As a paradigm with the protein lysine methyltransferase (PKMT) SET7/9 paired with its physiological substrates H3 and p53, their TSs were solved with experimental kinetic isotope effects as computational constraints. Remarkably, SET7/9 adopts two structurally distinct TSs, a nearly symmetric S(N)2 and an extremely early S(N)2, for H3K4 and p53K372 methylation, respectively. The two TSs are also different from those previously revealed for other PKMTs. The setting of multiple TSs is expected to be essential for SET7/9 and likely other PKMTs to act on broad substrates with high efficiency. |
| Keywords: | methyltransferase; probes; mechanism; specificity; analogs |
| Journal Title: | Journal of the American Chemical Society |
| Volume: | 141 |
| Issue: | 20 |
| ISSN: | 0002-7863 |
| Publisher: | American Chemical Society |
| Date Published: | 2019-05-22 |
| Start Page: | 8064 |
| End Page: | 8067 |
| Language: | English |
| ACCESSION: | WOS:000469292300011 |
| DOI: | 10.1021/jacs.9b02553 |
| PROVIDER: | wos |
| PMCID: | PMC6613214 |
| PUBMED: | 31034218 |
| Notes: | Article -- Source: Wos |
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