Key Factors for “Fishing” NTCP as a Functional Receptor for HBV and HDV

About ten years ago, Wenhui Li’s research group in China identified the sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter predominantly expressed in the liver, as a functional receptor for hepatitis B virus (HBV) and its satellite hepatitis delta virus (HDV) through biochemical and genetic studies. This finding unraveled a longtime mystery in the HBV field and led to the establishment of efficient and easy-to-use HBV infection models, which paved the way for the in-depth study of the HBV entry mechanism and facilitated the development of therapeutics against HBV and HDV. The whole picture of the complex HBV entry process became clear upon the follow-up studies over the years, including the recent resolution found for the NTCP structure. As one of the first authors of the 2012 eLife paper on NTCP identification, here, I (H. Y.) share our experience on the bumpy and exciting journey of receptor hunting, particularly on the photo-cross-linking study and some detailed descriptions of the “fishing” process and summarize the key factors for our successful receptor identification. This review may also provide helpful insights for identifying a protein target by peptide or protein baits through cross-linking and immunoprecipitation.