Co-Crystallization Study of LovB Con with Transition State Analogue
Stephanie S. Tu
Mentors: Shiou-Chuan (Sheryl) Tsai, David Jackson
Lovastatin was the first statin approved by the FDA and remains an important drug in the prevention and
treatment of cardiovascular diseases by lowering cholesterol production. The goal of this project was to
determine the residues in the condensation domain (Con) of the enzyme LovB that are required for the
catalysis of the Diels-Alder cyclization step in the biosynthesis of lovastatin. There is currently a lack of
structural information on enzymes that catalyze this type of cyclization activity. Thus, the aim of this project
is to provide insight into the molecular basis for this activity by solving a co-crystal structure of the Con
domain in complex with a stable transition state analogue. A putative co-crystal was grown and diffracted, but
when its structure was solved using molecular replacement, there was no electron density corresponding to
the transition state analogue. In conclusion, this crystallization condition was not suitable for cocrystallization, so crystallization conditions will be further optimized in the future. Once this complex
structure is solved, we will engineer the enzyme to accept different substrates by using site-directed
mutagenesis in order to improve the efficiency of the synthesis of a wide range of compounds involving
Diels-Alder reactions.