Abstract Dr. X. Huang
Title of Project Computational and Biological Co-design – Cracking UGT Structure-Function Relationships
The immediate need for understanding protein structure intensifies as the applications for engineered proteins for drugs, carriers, enzymatic activities, receptors, vaccines, antibodies, biomaterials and nanotechnology, in vitro synthesis, and detection systems grow. There is great utility in being able to input primary protein sequences and predict protein structure-function relationships for rational protein or drug design. Current computational approaches provide limited accuracy (~80%), often cannot handle large proteins, and require significant computational time. The proposed research will develop novel approaches for protein structure prediction to improve predictive accuracy and computational efficiency. Our strategy incorporates a “co-design” process enabling computational predictions to be directly tested and further optimized through a facile biological model of significant medical relevance—the UDP-glucuronosyltransferase (UGT) family.
UGTs are enzymes that
glucuronidate a variety of endogenous compounds, environmental pollutants, and
small molecule drugs leading to detoxification and/or clearance from the body.
Their fundamental role in metabolizing drugs such as azidothymidine (AZT) and
warfarin and impacting drug efficacy and dose (Miller et al., 2008) highlights
their medical importance. In addition, studies by Anna Radominska-Pandya, PhD,
et al. indicate that UGT levels are reduced or absent in ovarian cancer cells
compared to corresponding normal cells and restoration of UGT2B7 in these cells
results in colony formation, cell growth arrest, and decreased cell
proliferation (Radominska-Pandya et al., 2000, Lu et al., 2005). Understanding
the structure-function relationships of UGTs and substrate/inhibitor binding may
lead to safer, more effective pharmacological agents for broad clinical
applications. Currently, no crystal structure of a complete UGT exists and
reports of computer-assisted molecular modeling of UGTs are limited (Coffman et
al., 2001, 2003). The unusual “plug and play” domain structure of UGTs, which
pairs variable substrate binding domains (exons I) with a common sugar binding
domain (exons II-V), provides a unique opportunity to exploit computational
modeling to study the structure function relationship of UGTs and UGT mutants
with their diverse substrates.