Our research is driven by a fundamental interest in understanding the molecular mechanisms of biological macromolecules, with a focus on membrane proteins, DNA replication, and the development of structural biology methods. Through interdisciplinary collaborations and a combination of biochemical, biophysical, and structural approaches, we aim to address important biological questions and contribute to the understanding of human health and disease.
From Purified to Native: Revisiting Membrane Proteins
Our research has long focused on unraveling the molecular mechanisms of membrane proteins, which play versatile physiological functions and account for over 60% of drug targets. Prior to joining HKUST, we determined the structures of several membrane proteins using X-ray crystallography and single-particle cryo-EM, including TMEM16s, TRP channels, and transporters. At HKUST, our efforts have continued to understand the molecular and regulatory mechanism of ion channels and transporters. These include the TMEM63 family of mechanosensitive ion channels (Qin et al., 2023), as well as transporters important for fertilization, using the classical structural biology strategies.
In parallel, we have been committed to developing new methodologies to study membrane proteins within their native cellular environment. We have successfully developed a vesicle-based method that preserves the native lipid environment for structural determination (Liu et al., 2025), and are now further improving it for broader applications. This allows us to revisit previously characterized membrane proteins and capture their functional states in a more physiological context, bridging the gap between high-resolution structures obtained from purified samples and their functional relevance in health and disease.
From Structure to Mechanism: Unraveling the Replisome
DNA replication is a tightly regulated process that ensures faithful duplication of the genome during each cell division. It relies on the replisome, a large protein complex composed of DNA helicase, DNA polymerase, and various accessory factors. In collaboration with the labs of Bik Tye and Yuanliang Zhai, we focus on elucidating the structural mechanisms of the replisome to gain a comprehensive understanding of the molecular machinery underlying DNA replication. We have successfully determined the structures of the human pre-replication complex (Li et al., 2023), the CMG helicase–leading strand DNA polymerase complex (Xu et al., 2023), and the origin recognition complex (Lam et al., 2025). These findings have made significant contributions to the field of DNA replication.
From Collaboration to Impact: Structural Virology and Beyond
Through collaborative projects, we have extended our expertise in structural biology to address important biological and biomedical questions. During the SARS-CoV-2 pandemic, we worked with the lab of Zhiwei Chen at HKUMed to unravel the molecular mechanisms of neutralizing antibodies against the spike protein, providing insights for vaccine development against emerging variants (Zhou et al., 2022; Luo et al., 2023). In collaboration with the lab of Qinglu Zeng, we determined the cryo-EM structure of the cyanophage P-SCSP1u, revealing the assembly mechanism of the capsid and the DNA gating mechanism in T7-like viruses (Cai et al., 2023).