Biophysics of Proteins for Human Health
Protein function is governed by dynamic conformational landscapes. We use HDX-MS, NMR spectroscopy, mutagenesis, and computational modeling to define how mutations, ligands, and post-translational modifications reshape structural communication in disease-relevant systems.
Estrogen Receptor α (ERα)
Estrogen receptor α drives the majority of hormone-responsive breast cancers, yet resistance to endocrine therapies remains a major clinical challenge. We investigate how ligand binding, phosphorylation, and clinically observed mutations reprogram interdomain communication in full-length ERα. Using time- and temperature-resolved HDX-MS integrated with computational modeling, we define dynamic vulnerabilities that underlie aberrant signaling and therapeutic resistance. Our goal is to translate conformational insight into new strategies for selectively modulating ERα activity in resistant disease.
DDX3X RNA Helicase
DDX3X is an RNA helicase implicated in cancer, neurodevelopmental disorders, and antiviral signaling. Disease-associated mutations often disrupt its tightly coordinated conformational transitions, leading to altered RNA processing and dysregulated cellular pathways. We investigate how these mutations perturb dynamic coupling between domains and rewire functional output. By integrating HDX-MS, mutagenesis, and structural modeling, we aim to identify mechanistic control points that can be leveraged for therapeutic modulation.
NRPS Systems & Modular Enzyme Interfaces
Nonribosomal peptide synthetases (NRPS) are dynamic, multi-domain assembly lines responsible for the biosynthesis of many clinically important natural products, including antibiotics and anticancer agents. We investigate how domain interfaces and conformational transitions coordinate catalysis across modules and how disruption of this communication limits biosynthetic efficiency and fidelity. By defining the dynamic principles that govern interdomain coupling, we aim to enable rational reprogramming of modular biosynthetic systems for the development of next-generation therapeutic compounds.