Robert N. Kirchdoerfer
205A Bock Laboratories
1525 Linden Drive
Madison, WI 53706-1534
B.S., University of Wisconsin-Madison
Ph.D., The Scripps Research Institute
Postdoctoral, The Scripps Research Institute (Saphire laboratory)
Postdoctoral, The Scripps Research Institute (Ward laboratory)
Structural and biochemical exploration of RNA virus entry and replication
Coronaviruses are RNA viruses that infect a large number of avian and mammalian host species including humans. Most notable amongst the coronavirus family are highly pathogenic SARS-CoV and MERS-CoV which crossed into humans from animal reservoirs. Additionally, many coronaviruses cause significant pathogenesis in animal livestock.
Coronaviruses are faced with many challenges to enter and replicate in host cells. Coronaviruses are encased in a lipid envelope and must fuse their envelope membranes with the host cell membrane. To accomplish this, they use specialized protein machines called viral fusion proteins. For some viruses like coronaviruses, these fusion proteins also recognize receptors on the host cell and are the target of the host antibodies. By studying these viral fusion proteins, we can better understand how viruses choose their target host cells and work their way inside. We use high-resolution cryo-electron microscopy and biophysical experiments to examine viral fusion proteins and their interactions with host receptors and antibodies. This will illuminate viral evolution and allow us to develop effective vaccines against these viruses.
Once inside host cells, viruses must copy their RNA genomes and produce instructions to create new viral proteins. Coronaviruses use a large multi-subunit complex of viral proteins containing a plethora of enzyme activities for these processes. Coronaviruses are unusual amongst RNA viruses in that they couple their RNA polymerases with an exonuclease to correct errors that occur during the course of viral replication. In addition to increasing the fidelity of viral replication, this exonuclease also makes coronaviruses naturally resistant to many nucleoside analog antivirals. We use a combination of structural biology, biochemistry and cell-based assays to study the mechanisms of viral RNA synthesis. This work will inform the design and characterization of novel antiviral drugs for treating emerging viral infections.
SARS-CoV spike protein binds to human ACE2: A domain within the trimeric SARS-CoV spike protein samples downwards and upwards conformations. Only in the upwards conformation can the spike protein recognize its host receptor ACE2 (orange). One of the strengths of single-particle cryo-electron microscopy is the capability to structurally observe multiple conformations and bound receptors within a single sample.
Areas of Expertise
- Microbial Biophysics & Virology
- Protein Folding Design & Function
- Structural Biology