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Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs

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Science  13 Jun 2003:
Vol. 300, Issue 5626, pp. 1763-1767
DOI: 10.1126/science.1085658
  • Fig. 1.

    3D structure of coronavirus Mpro. (A) Monomer of HCoV Mpro. Domains I (top), II, and III (bottom) are indicated. Helices are red and strands are green. α helices are labeled A to F according to occurence along the primary structure, with the additional one-turn A′ α helix in the N-terminal segment (residues 11 to 14). β strands are labeled a to f, followed by an indication of the domain to which they belong (I or II). The N and C termini are labeled N and C, respectively. Residues of the catalytic dyad, Cys144 and His41, are indicated. (B) Structure-based sequence alignment of the main proteinases of coronaviruses from all three groups. HCoV, human coronavirus 229E (group I); TGEV, porcine transmissible gastroenteritis virus (group I); MHV, mouse hepatitis virus (group II); BCoV, bovine coronavirus (group II); SARS-CoV, SARS coronavirus (between groups II and III); IBV, avian infectious bronchitis virus (group III). The autocleavage sites of the proteinases are marked by vertical arrows above the sequences. In addition to the sequences of the mature enzymes, four residues each of the viral polyprotein N-terminal to the first and C-terminal to the second autocleavage site are shown. Note the conservation of the cleavage pattern, (small)-Xaa-Leu-Gln↓(Ala,Ser,Gly). Thick bars above the sequences indicate α helices (labeled A′ and A to F); horizontal arrows indicate β strands (labeled a to f, followed by the domain to which they belong). Residue numbers for HCoV Mpro are given below the sequence; three-digit numbers are centered about the residue labeled. Symbols in the second row below the alignment mark residues involved in dimerization of HCoV and TGEV Mpro: open circle (o) indicates only main chain involved; asterisk (*) indicates only side chain involved; plus (+) indicates both main chain and side chain involved. From the almost absolute conservation of side chains involved in dimerization, it can be concluded that SARS-CoV Mpro also has the capacity to formdimers. In addition, side chains involved in inhibitor binding in the TGEV Mpro complex are indicated by triangles (Δ), and catalytic-site residues Cys144 and His41 as well as the conserved Y160MH162 motif are shaded. (C) Cα plot of a monomer of SARS-CoV Mpro as model-built on the basis of the crystal structures of HCoV 229E Mpro and TGEV Mpro. Residues identical in HCoV Mpro and SARS-CoV Mpro are indicated in red.

  • Fig. 2.

    Dimer of HCoV Mpro. The N-terminal residues of each chain squeeze between domains II and III of the parent monomer and domain II of the other monomer. N and C termini are labeled by cyan and magenta spheres and the letters N and C, respectively.

  • Fig. 3.

    (A) Refined model of the TGEV Mpro-bound hexapeptidyl CMK inhibitor built into electron density (2∥Fo| – |Fc∥, contoured at 1σ above the mean). There was no density for the Cbz group or for the Cβ atomof the P1 Gln. Inhibitor is shown in red, protein in gray. Cys144 is yellow. (B) Inhibitors will bind to different coronavirus Mpros in an identical manner. A superimposition (stereo image) of the substrate-binding regions of the free enzymes of HCoV Mpro (blue) and SARS-CoV Mpro (gray) and of TGEV Mpro (green) in complex with the hexapeptidyl CMK inhibitor (red) is shown. The covalent bond between the inhibitor and Cys144 of TGEV Mpro is in purple.

  • Fig. 4.

    Derivatives of the antirhinoviral drug AG7088 should inhibit coronavirus Mpros. A superimposition (stereo image) of the substrate-binding regions of TGEV Mpro (marine) in complex with the hexapeptidyl CMK inhibitor (red) and HRV2 3Cpro (green) in complex with the inhibitor AG7088 (yellow) is shown.

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  • Abstract
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    Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs
    Kanchan Anand, John Ziebuhr, Parvesh Wadhwani, Jeroen R. Mesters, Rolf Hilgenfeld

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    Materials and Methods
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