The National Facility for Protein Science in Shanghai (NFPSS) recently supported the collaborative research team led by Academician Zihe Rao (Tsinghua University/ShanghaiTech University), Professor Wang Quan (ShanghaiTech University), and Researcher Hu Zhongyu (National Institutes for Food and Drug Control) in resolving the three-dimensional structure of the hepatitis B surface antigen (HBsAg). The research paper titled "Inherent symmetry and flexibility in hepatitis B virus subviral particles" was published in Science at 2:00 AM Beijing Time on September 13, 2024.
HBsAg is the critical protein determining viral invasion, replication, and packaging, while also serving as the essential diagnostic marker for infection and clinical functional cure assessment. In infection surveillance, HBsAg is the common marker in HBV "Big Three" and "Small Three" immunodiagnostics. Clinically, HBsAg clearance is the key indicator of chronic hepatitis B clinical cure. As the primary component of recombinant HBV vaccines and the main target of neutralizing antibodies, HBsAg holds vital significance for hepatitis B prevention and treatment.
Although extensively studied since the virus's discovery, the protein's complex structural features and polymorphic assembly remained long-standing mysteries in structural biology and virology. Academician Rao and Researcher Hu initiated HBsAg structural studies twenty years ago. In 2020, Professor Wang Quan (Academician Rao's former student) joined ShanghaiTech University and carried forward this persistent research into HBsAg's structure. Professor Wang's team utilized multiple NFPSS technical systems including the Large-scale Protein Preparation System, Electron Microscopy Analysis System, and Mass Spectrometry Analysis System. Through five years of intensive effort, leveraging profound expertise in cryo-EM single-particle analysis theory and innovative analytical software development, the team finally resolved HBsAg's 3D structure using specialized algorithms, revealing the molecular basis of its diverse oligomeric formations on viral particles.
This breakthrough not only solves a longstanding puzzle in structural biology and virology, but also provides crucial foundations for optimizing HBV recombinant vaccines and understanding neutralizing antibody structure-activity relationships. It particularly accelerates the development of small-molecule drugs directly targeting viral surface proteins and envelope assembly, along with PROTAC (PROteolysis TArgeting Chimera) degraders. This unlocks a novel strategic pathway for hepatitis B control, potentially ushering in a new era of HBV treatment.
