My research has been focusing on the structural and mechanistic investigation of membrane proteins of physiological and pathophysiological significance. During my PhD study, I mainly focused on the Scap/Insig complex, the critical sterol sensor in the sterol regulatory element-binding protein (SREBP) pathway, for X-ray crystallography, cryo-EM, and biochemical analyses. I almost spent my entire PhD years on the generation and optimization of this extremely challenging membrane protein complex. Eventually, combining advanced cryo-EM data processing and extensive biochemical and cellular characterizations, my co-workers and I were able to resolve the structure of the human Scap/Insig-2 complex and revealed the mechanism of sterol sensing by Scap and Insig [Yan et al, Science, 2021]. During this period, I also performed structural and biochemical characterizations of SEIPIN, a regulator for lipid droplet formation, and the human acyl-coenzyme A: cholesterol acyltransferase ACAT1 [Yan et al. Dev Cell, 2018; Qian et al. Nature, 2020].
My earlier work during postdoctoral research has been centered around human heteromeric amino acid transporters for structural and mechanistic elucidation. We solved the first structure of human amino acid transporter complex, LAT1-4F2hc, which is a well-known anti-tumor target for drug discovery [Yan et al. Nature, 2019]. To investigate the modulation of the amino acid transporter complex, I attempted to resolve the neutral amino acid transporter B0AT1 with its chaperon ACE2. Just around this time, there was the COVID-19 outbreak in Wuhan and ACE2 was reported to be the surface receptor of SARS-CoV-2. I immediately returned from my spring festival vacation and solved the structures of receptor binding domain of SARS-CoV-2 Spike (S) protein in complex with full-length ACE2- B0AT1 [Yan et al. Science. 2020]. This timely report that revealed the details of the interaction between the viral S protein and its cellular receptor has been cited by more than 3300 times according to Google Scholar.