The Experimental Structural Biology Section investigates the molecular mechanisms that control immune defense, restrict viral infections, and contribute to cancer development.
Controlling biomolecular function for therapeutic innovation
We use structural biology, biochemistry, and inhibitor design to uncover how biomolecules work and how controlling their activities can lead to new therapeutic strategies.
Atomic-level insights for targeted therapeutics
We uncover molecular mechanisms at atomic resolution using cutting-edge technologies, paving the way for the development of precise, targeted therapeutics.
Cryo-EM structure of the A3G-RNA-Vif-CBFβ complex
Cryo-EM structure of the cpzA3H- Vif-CBFβ-EloB&C complex
Structural insights into APOBEC3 function in immunity and cancer
Our current research focuses on elucidating the structural basis of APOBEC3 (A3) proteins’ single-stranded DNA cytosine deaminase activity, which plays key roles in HIV-1 restriction, tumor development, and cancer drug resistance.
APOBEC3 proteins and HIV in virus-host evolutionary arms race
A3 proteins can deaminate cytidines to 2′-deoxyuridines in single-stranded DNA. Through this activity, A3G, A3F, and A3H restrict HIV infection. In turn, HIV evolved the virion infectivity factor (Vif) to neutralize these enzymes by hijacking a host E3 ubiquitin ligase, which leads A3 proteins for proteasomal degradation.
Recently, we determined the cryo-EM structures of the A3G–Vif–CBFβ complex and the A3H–Vif–CBFβ–ElonginB&C complex, revealing how Vif counteracts host restriction.
APOBEC3 activity and cancer
Although A3 proteins play key roles in immunity, their mutagenic activity can also drive cancer development. A3A and A3B are major sources of mutations in several cancers, including breast, bladder, head and neck, cervical, and lung cancers. Inhibiting these enzymes could help slow cancer progression and improve chemotherapy effectiveness by reducing drug resistance. Recently, we determined a co-crystal structure of the active A3G catalytic domain bound to a DNA oligomer containing 2′-deoxy zebularine (dZ-ssDNA) and developed dZ-ssDNA inhibitors targeting A3A, which potently suppress its activity (Ki < 50 nM).