Structural insights into SARS coronavirus proteins

Abstract

The SARS coronavirus was identified as the pathogen of a global outbreak of SARS (severe acute respiratory syndrome) in 2003. Its large RNA genome encodes four structural proteins, sixteen non-structural proteins and eight accessory proteins. The availability of structures of SARS coronavirus macromolecules has enabled the elucidation of their important functions, such as mediating the fusion of viral and host cellular membranes, and in replication and transcription. In particular, the spike protein fusion core and the main protease have been the most extensively studied, with the aim of designing anti-SARS therapeutics. Attention is now being focused on replicase proteins, which should enhance our understanding of the replication and transcription machinery. The structures and functions of most SARS proteins remain unknown, and further structural studies will be important for revealing their functions and for designing potential anti-SARS therapeutics.

Figure 1

The SARS-CoV S protein fusion core. (a) Comparison of four ‘six-helix bundle’ structures. Shown from left to right are S protein fusion cores 1WYY [18], 2BEZ [17^•], 1WNC [9^••] and 2BEQ [9^••]. The central HR1 peptides are shown in ribbon representation, and are coloured red, blue and green. The HR2 peptides are shown in black. The N and C termini are labelled. (b) Comparison of four ‘HR1+HR2’ constructs, corresponding to the structures in (a). The labelled residues correspond to the start and end residues of the HR1 (red) and HR2 (black) peptides. (Figure adapted from [18].)

Figure 2

Other structures of SARS-CoV proteins. (a) Solution structure of the N-terminal RNA-binding domain of the SARS-CoV N protein (PDB code 1SSK). (b) X-ray crystal structure of nsp9, an ssRNA-binding protein (PDB code 1UW7). (c) X-ray crystal structure of the accessory protein Orf7a (PDB code 1XAK). (d) X-ray crystal structure of the s2m, a rigorously conserved RNA element of the SARS-CoV genome.

Figure 3

Nsp5, the SARS-CoV M^pro. (a) The crystal structure of SARS-CoV M^pro in complex with a CMK inhibitor (PDB code 1UKW). Protomers A and B are shown in ribbon representation, and are coloured red and blue, respectively. The CMK inhibitors are shown in yellow stick representation. The N-finger, residues 1–7 of protomer B, is shown in green. A transparent molecular surface is shown covering the structure. (b) Schematic of the SARS-CoV M^pro dimer, corresponding to the view in (a). Residue S1 on the N-finger of protomer B forms hydrogen bonds with two residues in protomer A, F140 and E166.