Oral Presentation Crystal36-AXAA Conference 2026

Biochemical and structural insights into the MNT:SIN3 interaction (142967)

Bhagya Mendis 1 2 , Cyrus Tan 1 2 , Ahmad Wardak 1 , Sean Smyth 1 , Hai Vu Nguyen 1 2 , Suzanne Cory 1 2 , Peter Czabotar 1 2 , Michelle S Miller 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia

MYC deregulation is a well-known driver of B and T cell lymphomas1, however, designing clinically effective small molecule inhibitors targeting MYC has been challenging2. MNT is a member of the MYC transcription network3 that contributes to MYC’s oncogenic activity in B and T cell lymphomas4, making it a potential alternative therapeutic target for MYC driven lymphomas. MNT acts by recruiting SIN3/HDAC complexes to repress transcription. Transcription factors, such as MNT, interact with SIN3 through binding of their SIN3 Interacting Domain (SID) to one of two SIN3 PAH (paired amphipathic helix) domains (PAH1 and PAH2)3-5. The hierarchy of affinities for SID – PAH domain interactions for the spectrum of partner transcription factors is yet to be established, primarily due to an absence of direct binding data for such interactions. Here we address this knowledge gap using affinity measurement via SPR to gain insight into this, and to place the binding affinity of MNT for SIN3 within the context of this wider transcription factor network. We find that the MNT SID binds tightly to SIN3 PAH2 domains at physiologically relevant binding affinities, as do the SID domains from other MXD family transcription factors (MXD1-4). To structurally characterise the MNT:SIN3 interaction, we determined a crystal structure of the MNT-SID bound to a SIN3 PAH2 domain. Comparing the MNT SID PAH2 interaction to that of the close relative MXD1 we observe similar binding modes, but with hydrogen bonding differences that provide a rationale for their distinct binding energies6. Overall, we have performed the first comparative assessment of SID binding to SIN3 PAH2 domains and have solved the first structure of MNT SID bound to a SIN3 PAH2 domain, providing insights into the targeting of such interfaces for potential therapeutics.

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