Project Details
Description
ABSTRACT
With the recent revolution in artificial intelligence for molecular design and protein structure
prediction, we were motivated to apply these new tools to address bottlenecks in our research
focusing on retroviral entry, integration, and drug design. Viral entry and receptor usage has
become a major focus with the emergence of new viruses with expanded host and tissue
specificities. Our research focuses on the ability of retroviral Envelopes to select and utilize novel
host cell receptors. In this proposal, we are utilizing new approaches to identify and study two
novel retroviral Env proteins and their host cell receptors. These include the binding of the A5/A9a
Env protein to the host membrane protein SLC35F2 and the identification of the cognate
receptor(s) for the L1 Env. Applying AlphaFold2, Phyre2 and Evolutionary Covariance structure
prediction programs, we have a first generation model for SLC35F2, which serves as the
foundation for a broad number of questions relating to the function of this orphan receptor. The
second area of focus builds on the gammaretroviral Integrase (IN) protein binding to the host BET
proteins. Through our structural studies of both the Murine Leukemia Leukemia (MLV) IN protein
and the host NSD3 protein binding to the ET domain of the Brd3 BET protein, we are now able to
apply our knowledge of the common binding pocket to advance approaches for studies of
alternative binding substrates and small molecule inhibitors. The ET domain of the BET family of
proteins serves as a node for multi-protein assemblies. Understanding the affinity of different
proteins and small molecules to this ET binding pocket can have profound effects of
gammaretroviral pathogenesis as well as gene and oncogene regulation. Using computer-aided
drug discovery approaches, we have identified first-in-class lead compounds targeting the ET
domain. These studies build on our cohesive collaborative research team with expertise in
virology, NMR structural studies, and bioinformatics.
Status | Finished |
---|---|
Effective start/end date | 9/30/17 → 12/31/24 |
Funding
- National Institute of General Medical Sciences: $565,200.00
- National Institute of General Medical Sciences: $26,599.00
- National Institute of General Medical Sciences: $332,691.00
- National Institute of General Medical Sciences: $66,982.00
- National Institute of General Medical Sciences: $644,288.00
- National Institute of General Medical Sciences: $630,341.00
- National Institute of General Medical Sciences: $630,341.00
- National Institute of General Medical Sciences: $630,341.00
- National Institute of General Medical Sciences: $630,341.00
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