Understanding how virus particles assemble
Lead researcher: Professor Fred Antson, Department of Chemistry
Viral infections caused by the family of herpes viruses, such as HSV1, Epstein-Barr, Cytomegalovirus and Varicella Zoster cause lifelong infections that are impossible to eradicate using current treatments. These viruses may remain dormant for years, hiding from the immune system, only to reactivate and cause illnesses later, often leading to serious health disorders including cancer.
During an active phase, new copies of the virus’ genes are made and loaded into capsids, as shown on figure , to make new virus particles that then burst out of the host and spread to other cells.
To understand the mechanism of virus assembly, the Antson group is using model systems derived from bacteriophages, close evolutionary relatives of herpes viruses. The main emphasis is to image molecular machines using cryo-electron microscopy and X-ray crystallography. The research provides detailed information about the structure of individual proteins, how they fit together and how they work [2,3]. The figure illustrates X-ray structures of three proteins (large and small terminases and the portal protein) that ensure packaging of the viral genome into empty pre-assembled capsids.
This research addresses the knowledge gap in the molecular interactions within protein-nucleic acid machines critical to viral replication and assembly. Knowledge of the architecture of these machines and the structure of their functional domains and active sites will help us understand the underlying molecular mechanisms. With such knowledge we can more effectively develop genetic and chemical intervention strategies against viral infections.
In the longer term, the research aims to translate structural and mechanistic findings into anti-viral therapies and nanomedical applications .
- Bayfield OW, Klimuk E, Winkler DC, Hesketh EL, Chechik M, Cheng N, Dykeman EC, Minakhin L, Ranson NA, Severinov K, Steven AC, Antson AA: Cryo-EM structure and in vitro DNA packaging of a thermophilic virus with supersized T=7 capsids. Proc. Natl. Acad. Sci. USA, 2019, accepted, in press.
- Xu RG, Jenkins HT, Antson AA, Greive SJ: Structure of the large terminase from a hyperthermophilic virus reveals a unique mechanism for oligomerization and ATP hydrolysis. Nucleic Acids Research, 2017, 45: 13029-13042.
- Büttner C, Chechik M, Ortiz-Lombardíaa M, Smits M, Ebong I-O, Chechik V, Jeschke G, Dykeman E, Benini S, Robinson CV, Alonso JC, Antson AA: Structural basis for DNA recognition and loading into a viral packaging motor. Proc. Natl. Acad. Sci. USA, 2012, 109:811-816.
- Cressiot B, Greive SJ, Si W, Mojtabavi M, Antson AA, Wanunu M: Thermostable Virus Portal Proteins as Reprogrammable Adapters for Solid-State Nanopore Sensors. Nature Communications, 2018, 9:4652.