Transcriptional coactivator myocyte enhancer factor 2B (MEF2B) mutations are the most common cause of germinal center-derived B-cell non-Hodgkin lymphoma. Despite well-established contributions in lymphomagenesis, the structure-function paradigms of these mutations are largely unknown. Here through in silico approaches, we present structural evaluation of two reported missense variants (K4E and Y69H) in MEF2B to investigate their impact on DNA-binding through molecular dynamics simulation assays. Notably, MEF2B-specific MADs box domain (Lys23, Arg24 and Lys31) and N-terminal loop residues (Gly2, Arg3, Lys4, Lys5, Ile6 and Asn13) contribute in DNA binding, while in MEF2B, DNA binding is facilitated by Gly2, Arg3 and Arg91 (α3) residues. Conversely, in MEF2B, Arg3, Lys5, Ser78, Arg79 and Asn81 residues mediate DNA binding. DNA binding induces pronounced conformational readjustments in MEF2B-specific α1-N-terminal loop region, while MEF2B and MEF2B exhibit fluctuations in both α1 and α3. Hydrogen (H)-bond occupancy analysis reveals a similar DNA binding behavior for MEF2 and MEF2B, compared to MEF2B structure. The Anisotropic Network Model analysis depicts α1 and α3 as more fluctuant regions in MEF2B as compared to other systems. MEF2B and MEF2B, Tyr69 residue is involved in p300 binding thus possible influence of Y69H variation in the functions other than DNA binding, such as p300 co-activator recruitment may explain the reduced transcriptional activation of MEF2B. Thus, present study may provide a structural basis of DNA recognition by pinpointing the underlying conformational changes in the dynamics of MEF2B, MEF2B, and MEF2B structures that may contribute in the identification of novel therapeutic strategies for lymphomagenesis.
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