D-107 Structure and Stabilization of Coronavirus Spike Proteins in the Prefusion Conformation

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Coronaviruses have the largest genomes among known RNA viruses and are phylogenetically divided into 4 genera. Some betacoronaviruses, such as HKU1, circulate annually in humans and cause mild yet prevalent respiratory disease whereas others, such as SARS-CoV and the recently emerged MERS-CoV, have caused pandemics with high case-fatality rates. Coronavirus cell tropism and host range are in large part determined by the viral surface spike (S) glycoprotein, which is the largest known class I viral fusion protein. After binding to host receptors and activation by host proteases, the S proteins undergo large conformational rearrangements that result in fusion of the viral and host-cell membranes. However, until recently, structural studies of the S proteins have been primarily limited to small protein fragments. Together with Andrew Ward and Barney Graham, we have initiated studies to provide a molecular understanding of the structure, function and antigenicity of intact, trimeric S proteins, which we believe will identify sites of vulnerability that could be targeted by vaccines, therapeutic antibodies and small-molecule antivirals. Our recent structure of the trimeric HKU1 S protein in its prefusion conformation will be presented, as well as the initial results of our structure-based vaccine design efforts.

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