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. 2004 Dec 28;101(52):17958-63.
doi: 10.1073/pnas.0406128102. Epub 2004 Dec 16.

Structure of a proteolytically resistant core from the severe acute respiratory syndrome coronavirus S2 fusion protein

Vinit M Supekar  1 , Chiara Bruckmann, Paolo Ingallinella, Elisabetta Bianchi, Antonello Pessi, Andrea Carfí
Affiliations

Structure of a proteolytically resistant core from the severe acute respiratory syndrome coronavirus S2 fusion protein

Vinit M Supekar et al. Proc Natl Acad Sci U S A. .

Abstract

A coronavirus (CoV) has recently been identified as the causative agent of the severe acute respiratory syndrome (SARS) in humans. CoVs enter target cells through fusion of viral and cellular membranes mediated by the viral envelope glycoprotein S. We have determined by x-ray crystallography the structure of a proteolytically stable core fragment from the heptad repeat (HR) regions HR1 and HR2 of the SARS-CoV S protein. We have also determined the structure of an HR1-HR2 S core fragment, containing a shorter HR1 peptide and a C-terminally longer HR2 peptide that extends up to the transmembrane region. In these structures, three HR1 helices form a parallel coiled-coil trimer, whereas three HR2 peptides pack in an oblique and antiparallel fashion into the coiled-coil hydrophobic grooves, adopting mixed extended and alpha-helical conformations as in postfusion paramyxoviruses F proteins structures. Our structure positions a previously proposed internal fusion peptide adjacent to the N-terminus of HR1. Peptides from the HR2 region of SARS-CoV S have been shown to inhibit viral entry and infection in vitro. The structures presented here can thus open the path to the design of small-molecule inhibitors of viral entry and candidate vaccine antigens against this virus.

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Figures

Fig. 1.
Fig. 1.
Organization and sequence alignments of CoV S HRs. (A) Schematic organization of CoVs S. The cleavage site in the related MHV S is shown. (B) Sequence alignment for the HR regions for CoV S2 proteins. Hydrophobic residues with a, d, and x packing in the HR1 HRs are indicated above the sequence.
Fig. 2.
Fig. 2.
Structure of the SARS-CoV S2 core. (A) Ribbon representation of the S2 core structure. (B) Irregularity in the 3–4 repetition of the HR1 trimer. (C) An HR1-HR2 heterodimer. HR1 is blue and HR2 is red. (D) Electrostatic potential surface of the HR1 inner coil trimer with HR2 peptides shown as a ball-and-stick representation packing on the trimer grooves; two conserved glycosylation sites predicted at N1155 and N1176 of HR2 are indicated.
Fig. 3.
Fig. 3.
A hydrophobic pocket on the surface of the HR1 trimer with residues V1146 and L1148 from HR2 pointing toward it.
Fig. 4.
Fig. 4.
Differences between MHV and SARS-CoV S2 core structures. (A) Mutation of the conserved Phe-981 of MHV (yellow) with Leu-920 in SARS-CoV S2 (blue). (B) Shift of the HR2 α-helices positions between MHV (yellow) and SARS-CoV S2 (red) after superposition of the HR1 trimer.
Fig. 5.
Fig. 5.
Ribbon representations of the N3/C2 complex and model of the postfusion structure of SARS-CoV S2. (A) The N3/C2 trimer. N3 is blue and C2 is red (B) An N3/C2 heterodimer, with highlighted “start and end” positions of secondary structure element. (C) Superposition between a HR1-HR2 heterodimer and a N3/C2 heterodimer. (D) Schematic representation of the proposed S2 postfusion structure.
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