Computational Investigation of Positive Cooperativity in the cMyb-KIX-MLL Ternary Complex

 

Suhani B. Patel
Dr. Bill Miller (ATSU) and Dr. Hanbo Hong, Faculty Mentors

The KIX domain of the CREB-binding protein (CBP) behaves as a transcriptional coactivator, mediating interactions of multiple transcription factors, including c-Myb and the mixed lineage leukemia protein (MLL). c-Myb plays a critical role in the proliferation and differentiation of hematopoietic cells. Experimental and computational studies have shown the binding of MLL to KIX increases the affinity of c-Myb. This results in a positively cooperative ternary complex through an allosteric mechanism, which is important in transcription regulation. An overexpression of c-Myb has been linked to cancer, especially acute myeloid leukemia (AML). In this study, computational chemistry methods were used to investigate the structural basis of this cooperativity, and identify potential small-molecule inhibitors targeting the c-Myb-KIX binding pocket. Drug-like compounds from the ZINC20 database were screened using molecular docking. Promising candidates were further evaluated using molecular dynamics simulations with the AMBER to assess binding stability and conformational effects on the KIX domain.

 

Keywords: Computational Chemistry, c-Myb, KIX, MLL, Linux, Molecular Dynamics, Leukemia, Novel Drugs

Topic(s):Biochemistry and Molecular Biology
Chemistry
Computer Science

Presentation Type: Oral Presentation

Session: TBA
Location: TBA
Time: TBA