Our laboratory is interested in understanding the structural and molecular mechanisms of key viral and cellular processes. Specifically, the thrust of our research is focused on three areas:
a) Virus-cell and cell-cell fusion.
The entry of enveloped viruses, such as influenza A, HIV-1, SARS-CoV, and Ebola virus and others, utilize viral glycoproteins on its surface to mediate cellular attachment, tropism, and viral-host membrane fusion.
Dramatic conformational changes in the glycoproteins, triggered through pH-dependent, pH-independent, or two-step mechanisms, are necessary for fusion.We are interested in understanding the molecular mechanisms of viral-cell membrane fusion in order to develop new antivirals that block viral entry.
The fusion of membranes is also important in many biological processes, such as fertilization (sperm-egg fusion), placenta development (trophoblast fusion), skeletal muscle development (myoblast fusion), bone development (osteoclast fusion), among other processes. The mechanisms of cell-cell fusion are poorly defined and have generally been based on the mechanisms employed by viruses for fusion. Recently, it seems some cell-cell fusion processes may be evolutionarily related to the viral glycoproteins (for example C. elegans EFF-1 protein, and syncytin-1/syncytin-2 in placenta development). We are interested in understanding the various mechanism of cell-cell fusion and how it relates to virus-cell fusion.
b) Anti-viral immune restriction factors.
Once a virus enters and fuses with the host cell, it uncoats and releases its genetic material for replication.
The human innate immune system has developed complex responses to prevent the spread of pathogens, such as HIV-1. APOBEC3 proteins act as host restriction factors to inhibit HIV-1 replication by deaminating ssDNA cytosine bases to result in uracil in the viral minus-strand DNA.
During plus-strand DNA synthesis, adenines, instead of guanines, are incorporated, leading to inactivation of the viral genome. HIV-1 antagonizes APOBEC3 by encoding for an accessory protein, termed Viral Infectivity Factor (Vif).
Vif hijacks the host E3 ubiquitin ligase machinery to polyubiquitinate APOBEC3 for proteasomal degradation. Our lab is interested in understanding how APOBEC3 act as HIV-1 restriction factors and how it is counteracted by HIV-1 Vif.
c) Discovery of anti-viral agents.
Using our structural models as a molecular blueprint, we aim to develop new therapeutic strategies to combat viruses.
Understanding the entry, and immunological restriction of viral pathogens is fundamental for fighting infectious disease.
The main tool we employ to understand cellular and viral protein function is X-ray crystallography. Crystallographic analysis of viral and cellular surface glycoproteins and restriction factors has offered a tremendous wealth of insights into recognition, entry, fusion, restriction, and pathogenesis. We also combine X-ray crystallography with other biophysical and biochemical techniques such as small angle X-ray scattering (SAXS) and deuterium exchange mass spectrometry (DXMS) to reach the higher hanging fruits. Once structures are determined, questions and hypotheses arising will be subsequently tested using biochemical, immunological and virological techniques. Our long-term goals are to understand the fundamental principles behind key biological processes, identify new targets and provide a template for the design and development of new therapeutic strategies.
Image: Complex of human Izumo1-Juno. Aydin et al. 2016. Nature. (Image Credit: Joy Qu)