Bitte benutzen Sie diese Kennung, um auf die Ressource zu verweisen: http://dx.doi.org/10.18419/opus-13226
Autor(en): Miranda-Rojas, Sebastián
Blanco-Esperguez, Kevin
Tuñón, Iñaki
Kästner, Johannes
Mendizábal, Fernando
Titel: Exploration of the activation mechanism of the epigenetic regulator MLL3 : a QM/MM study
Erscheinungsdatum: 2021
Dokumentart: Zeitschriftenartikel
Seiten: 21
Erschienen in: Biomolecules 11 (2021), No. 1051
URI: http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-ds-132453
http://elib.uni-stuttgart.de/handle/11682/13245
http://dx.doi.org/10.18419/opus-13226
ISSN: 2218-273X
Zusammenfassung: 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.
Enthalten in den Sammlungen:03 Fakultät Chemie

Dateien zu dieser Ressource:
Datei Beschreibung GrößeFormat 
biomolecules-11-01051-v3.pdf10,02 MBAdobe PDFÖffnen/Anzeigen


Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons Creative Commons