Research

Human p53 plays a central role in suppressing tumors, and its dysfunctional mutations are present in over 50% of human cancers. The full-length p53 consists of unstructured and structured domains and can form monomers, dimers, or tetramers at physiological concentrations. The dynamic interactions among these domains are critical for p53 to function properly, including binding and releasing recognition-element DNAs in response to time-dependent post-translational modifications.  We aim to answer the following questions:

• How do unstructured motifs dynamically interact with structured DNA-binding domains in p53 dimers and tetramers? 

• How do oncogenic mutations and post-translational modifications influence the conformational ensemble of p53?

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large class of natural products, including antimicrobial lantibiotics active against some multidrug-resistant bacteria. RiPP biosynthetic pathways are defined by sequential biochemical reactions to form modified peptides with highly regio- and stereo-specific chemical motifs.  The dynamic interactions between peptide substrates and biosynthetic enzymes are essential to drive the multistep biosynthesis of RiPPs. We are interested in probing the following questions:

• How do RiPP synthetases coordinate multiple conformations to drive sequential biochemical reactions?

• How are the regio- and stereo-specificities enforced for substrate peptides during RiPP biosynthesis?