Research Interests

The focus of our research is centered around using both experimental and computational techniques to study estrogen receptor—a dominant driver of most breast cancers—and on technology development of new approaches for structural biology, especially state-of-the-art synchrotron biophysical techniques.

Current efforts in the lab include (but not limited to):

1. Integrated Structural Biology by iSPOT

Despite decades of effort, structure determination of protein-protein interacting complexes, the molecular underpinning for virtually every biological process, is still a daunting task for conventional techniques. To advance the ability in characterizing such complexes, we have established an integrated multi-technique iSPOT platform by combining computational docking and experimental scattering and footprinting techniques. The iSPOT enables the structure determination of protein-protein complexes (typically in the range of 50-200 kDa) that are challenging for conventational techqniques. This development is a result of a body of new data analysis algorithms and computational software we developed (e.g., Fast-SAXS-pro for scattering computation and footprinting-based protection-factor analysis).

2. Biophysics of ER allosteric cross-talk

Estrogen receptor alpha (ER), a key driver for the majority of breast cancer, consists of two functional domains (i.e., DNA-binding and ligand-binding) critical for hormonal signaling. A fundamental question, however, remains elusive with regard to how these two domains interact with each other at the molecular level. Through multiple biophysical approaches and computational modeling, we have determined a median-resolution structure of the ER multidomain complex. This discovery has uncovered a protein fold of the multidomain ER complex that is completely new, compared to other currently known nuclear hormone receptors, revealing the hidden cross-talk between ER's functional domains. Ultimately, the work provides a molecular basis for targeting ER to tackle acquired resistance in antiestrogen therapy.

3. Protein-induced folding of ER N-terminus

The N-terminal domain (NTD) of ER is intrinsically unstructured, but induced by interaction with other protein to undergo large-scale folding changes. While the LBD has been extensively studied, structural and molecular properties of the NTD are largely unknown, but critical for understanding its hormone-independent transactivation. We have used biochemical approaches, molecular simulations, and structural biology techniques to examine the folding mechansism of this intrinsically disordered NTD upon molecular binding and to identify the NTD surface available for molecular recognition.

4. Software development

i. Fast-SAXS-pro

ii. A simple Protection Factor weblet

iii. More to come