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Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study

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Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study

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dc.contributor.author	Miranda-Rojas, Sebastián
dc.contributor.author	Blanco-Esperguez, Kevin
dc.contributor.author	Tuñón, Iñaki
dc.contributor.author	Kästner, Johannes
dc.contributor.author	Mendizábal, Fernando
dc.date.accessioned	2022-04-27T12:55:25Z
dc.date.available	2022-04-27T12:55:25Z
dc.date.issued	2021
dc.identifier.citation	Miranda-Rojas, Sebastián Blanco-Esperguez, Kevin Tuñón, Iñaki Kästner, Johannes Mendizábal, Fernando 2021 Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study Biomolecules 11 7 1051 1072
dc.identifier.uri	https://hdl.handle.net/10550/82432
dc.description.abstract	The mixed lineage leukemia 3 or MLL3 is the enzyme in charge of the writing of an epigenetic mark through the methylation of lysine 4 from the N-terminal domain of histone 3 and its deregulation has been related to several cancer lines. An interesting feature of this enzyme comes from its regulation mechanism, which involves its binding to an activating dimer before it can be catalytically functional. Once the trimer is formed, the reaction mechanism proceeds through the deprotonation of the lysine followed by the methyl-transfer reaction. Here we present a detailed exploration of the activation mechanism through a QM/MM approach focusing on both steps of the reaction, aiming to provide new insights into the deprotonation process and the role of the catalytic machinery in the methyl-transfer reaction. Our finding suggests that the source of the activation mechanism comes from conformational restriction mediated by the formation of a network of salt-bridges between MLL3 and one of the activating subunits, which restricts and stabilizes the positioning of several residues relevant for the catalysis. New insights into the deprotonation mechanism of lysine are provided, identifying a valine residue as crucial in the positioning of the water molecule in charge of the process. Finally, a tyrosine residue was found to assist the methyl transfer from SAM to the target lysine.
dc.language.iso	eng
dc.relation.ispartof	Biomolecules, 2021, vol. 11, num. 7, p. 1051-1072
dc.subject	Càncer
dc.subject	Proteïnes
dc.title	Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study
dc.type	journal article	es_ES
dc.date.updated	2022-04-27T12:55:26Z
dc.identifier.doi	10.3390/biom11071051
dc.identifier.idgrec	151885
dc.rights.accessRights	open access	es_ES