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Severe acute respiratory syndrome coronavirus (SARS-CoV) is a newly emergent virus responsible for a worldwide epidemic in 2003. The coronavirus spike proteins belong to class I fusion proteins, and are characterized by the existence of two heptad repeat (HR) regions, HR1 and HR2. The HR1 region in coronaviruses is predicted to be considerably longer than that in other type I virus fusion proteins. Therefore the exact binding sequence to HR2 from the HR1 is not clear. In this study, we defined the region of HR1 that binds to HR2 by a series of biochemical and biophysical measures. Subsequently the defined HR1 (902-952) and HR2 (1145-1184) chains, which are different from previously defined binding regions, were linked together by a flexible linker to form a single-chain construct, 2-Helix. This protein was expressed in Escherichia coli and forms a typical six-helix coiled coil bundle. Highly conserved HR regions between mouse hepatitis virus (MHV) and SARS-CoV spike proteins suggest a similar three-dimensional structure for the two fusion cores. Here, we constructed a homology model for SARS coronavirus fusion core based on our biochemical analysis and determined the MHV fusion core structure. We also propose an important target site for fusion inhibitor design and several strategies, which have been successfully used in fusion inhibitor design for human immunodeficiency virus (HIV), for the treatment of SARS infection.

Original publication

DOI

10.1021/bi049101q

Type

Journal article

Journal

Biochemistry

Publication Date

09/11/2004

Volume

43

Pages

14064 - 14071

Keywords

Amino Acid Sequence, Binding Sites, Computer Simulation, Genetic Vectors, Membrane Glycoproteins, Models, Molecular, Molecular Sequence Data, Murine hepatitis virus, Peptide Fragments, Peptides, Protein Binding, Protein Engineering, Protein Structure, Secondary, Recombinant Fusion Proteins, Repetitive Sequences, Amino Acid, SARS Virus, Solubility, Spike Glycoprotein, Coronavirus, Structural Homology, Protein, Viral Envelope Proteins, Viral Fusion Proteins