Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α‐helical domain
Identifieur interne : 000612 ( Istex/Curation ); précédent : 000611; suivant : 000613Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α‐helical domain
Auteurs : Kanchan Anand [Allemagne] ; Gottfried J. Palm [Allemagne] ; Jeroen R. Mesters [Allemagne] ; Stuart G. Siddell [Allemagne] ; John Ziebuhr [Allemagne] ; Rolf Hilgenfeld [Allemagne]Source :
- The EMBO Journal [ 0261-4189 ] ; 2002-07-01.
English descriptors
- Teeft :
- 3cpro, Aaaggatccttatgacatgacattagtaccttccaattg atggcacagcctagtggtcttgta, Acta crystallogr, Active site, Active site cleft, Amino, Amino acid residues, Ammonium sulfate, Asymmetric, Asymmetric unit, Bergmann, Biol, Catalytic, Catalytic centre, Catalytic site, Catalytic triad, Chymotrypsin, Cleavage, Cleavage sites, Coding sequence, Coronavirus, Coronavirus mpro, Crystal structure, Crystal structures, Crystallization medium, Crystallogr, Cysteine, Cysteine proteinases, Data collection, Data sets, Diffraction beamline, Diffraction data, Dimer, Domain, Electron density, Electron density maps, Embl outstation, Enzymatic activities, Experimental data, Febs lett, Gene product, Glutamine, Glutamine side chain, Hcov, Hegyi, Helix, Histidine, Histidine residues, Human coronavirus, Human rhinovirus, Hydrogen bond, Hydrogen bonds, Hydrophobic, Hydrophobic pocket, Hydrophobic residues, Hydroxyl group, Imidazole side chain, Loop region, Main chain, Main chain amides, Molecular modelling, Molecule, Monomer, Mpro, Mpro residues, Mpro structure, Mpro substrates, Mutagenesis, Mutant, Mutant proteins, Mutational analysis, Mutual arrangement, Natl acad, Neutral state, Nucleic acids, Other members, Other monomers, Outer wall, Oxyanion hole, Peak wavelengths, Peptide, Peptide inhibitors, Phase problem, Picornavirus, Proper orientation, Protease, Protein structures, Proteinase, Proteinase activity, Proteolytic, Proteolytic activities, Proteolytic activity, Proteolytic processing, Proteolytic products, Quality indicator, Recombinant proteins, Remote wavelengths, Replicase polyproteins, Replicative polyproteins, Residue, Salt bridge, Scissile bond, Secondary structure elements, Serine, Serine proteases, Serine proteinases, Side chain, Side chains, Solvent content, Structural information, Structure determination, Structure factors, Subsite, Substrate binding, Sulfur atom, Tgev, Tgev mpro, Tgev mpro autoprocessing site, Tgev mpro crystal structure, Third member, Transmissible gastroenteritis virus, Unit cell dimensions, Viral, Viral cysteine proteinase, Virol, Virology, Water molecule, Water molecules, Ziebuhr.
Abstract
The key enzyme in coronavirus polyprotein processing is the viral main proteinase, Mpro, a protein with extremely low sequence similarity to other viral and cellular proteinases. Here, the crystal structure of the 33.1 kDa transmissible gastroenteritis (corona)virus Mpro is reported. The structure was refined to 1.96 Å resolution and revealed three dimers in the asymmetric unit. The mutual arrangement of the protomers in each of the dimers suggests that Mpro self‐processing occurs in trans. The active site, comprised of Cys144 and His41, is part of a chymotrypsin‐like fold that is connected by a 16 residue loop to an extra domain featuring a novel α‐helical fold. Molecular modelling and mutagenesis data implicate the loop in substrate binding and elucidate S1 and S2 subsites suitable to accommodate the side chains of the P1 glutamine and P2 leucine residues of Mpro substrates. Interactions involving the N‐terminus and the α‐helical domain stabilize the loop in the orientation required for trans‐cleavage activity. The study illustrates that RNA viruses have evolved unprecedented variations of the classical chymotrypsin fold.
Url:
DOI: 10.1093/emboj/cdf327
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<term>Aaaggatccttatgacatgacattagtaccttccaattg atggcacagcctagtggtcttgta</term>
<term>Acta crystallogr</term>
<term>Active site</term>
<term>Active site cleft</term>
<term>Amino</term>
<term>Amino acid residues</term>
<term>Ammonium sulfate</term>
<term>Asymmetric</term>
<term>Asymmetric unit</term>
<term>Bergmann</term>
<term>Biol</term>
<term>Catalytic</term>
<term>Catalytic centre</term>
<term>Catalytic site</term>
<term>Catalytic triad</term>
<term>Chymotrypsin</term>
<term>Cleavage</term>
<term>Cleavage sites</term>
<term>Coding sequence</term>
<term>Coronavirus</term>
<term>Coronavirus mpro</term>
<term>Crystal structure</term>
<term>Crystal structures</term>
<term>Crystallization medium</term>
<term>Crystallogr</term>
<term>Cysteine</term>
<term>Cysteine proteinases</term>
<term>Data collection</term>
<term>Data sets</term>
<term>Diffraction beamline</term>
<term>Diffraction data</term>
<term>Dimer</term>
<term>Domain</term>
<term>Electron density</term>
<term>Electron density maps</term>
<term>Embl outstation</term>
<term>Enzymatic activities</term>
<term>Experimental data</term>
<term>Febs lett</term>
<term>Gene product</term>
<term>Glutamine</term>
<term>Glutamine side chain</term>
<term>Hcov</term>
<term>Hegyi</term>
<term>Helix</term>
<term>Histidine</term>
<term>Histidine residues</term>
<term>Human coronavirus</term>
<term>Human rhinovirus</term>
<term>Hydrogen bond</term>
<term>Hydrogen bonds</term>
<term>Hydrophobic</term>
<term>Hydrophobic pocket</term>
<term>Hydrophobic residues</term>
<term>Hydroxyl group</term>
<term>Imidazole side chain</term>
<term>Loop region</term>
<term>Main chain</term>
<term>Main chain amides</term>
<term>Molecular modelling</term>
<term>Molecule</term>
<term>Monomer</term>
<term>Mpro</term>
<term>Mpro residues</term>
<term>Mpro structure</term>
<term>Mpro substrates</term>
<term>Mutagenesis</term>
<term>Mutant</term>
<term>Mutant proteins</term>
<term>Mutational analysis</term>
<term>Mutual arrangement</term>
<term>Natl acad</term>
<term>Neutral state</term>
<term>Nucleic acids</term>
<term>Other members</term>
<term>Other monomers</term>
<term>Outer wall</term>
<term>Oxyanion hole</term>
<term>Peak wavelengths</term>
<term>Peptide</term>
<term>Peptide inhibitors</term>
<term>Phase problem</term>
<term>Picornavirus</term>
<term>Proper orientation</term>
<term>Protease</term>
<term>Protein structures</term>
<term>Proteinase</term>
<term>Proteinase activity</term>
<term>Proteolytic</term>
<term>Proteolytic activities</term>
<term>Proteolytic activity</term>
<term>Proteolytic processing</term>
<term>Proteolytic products</term>
<term>Quality indicator</term>
<term>Recombinant proteins</term>
<term>Remote wavelengths</term>
<term>Replicase polyproteins</term>
<term>Replicative polyproteins</term>
<term>Residue</term>
<term>Salt bridge</term>
<term>Scissile bond</term>
<term>Secondary structure elements</term>
<term>Serine</term>
<term>Serine proteases</term>
<term>Serine proteinases</term>
<term>Side chain</term>
<term>Side chains</term>
<term>Solvent content</term>
<term>Structural information</term>
<term>Structure determination</term>
<term>Structure factors</term>
<term>Subsite</term>
<term>Substrate binding</term>
<term>Sulfur atom</term>
<term>Tgev</term>
<term>Tgev mpro</term>
<term>Tgev mpro autoprocessing site</term>
<term>Tgev mpro crystal structure</term>
<term>Third member</term>
<term>Transmissible gastroenteritis virus</term>
<term>Unit cell dimensions</term>
<term>Viral</term>
<term>Viral cysteine proteinase</term>
<term>Virol</term>
<term>Virology</term>
<term>Water molecule</term>
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<front><div type="abstract">The key enzyme in coronavirus polyprotein processing is the viral main proteinase, Mpro, a protein with extremely low sequence similarity to other viral and cellular proteinases. Here, the crystal structure of the 33.1 kDa transmissible gastroenteritis (corona)virus Mpro is reported. The structure was refined to 1.96 Å resolution and revealed three dimers in the asymmetric unit. The mutual arrangement of the protomers in each of the dimers suggests that Mpro self‐processing occurs in trans. The active site, comprised of Cys144 and His41, is part of a chymotrypsin‐like fold that is connected by a 16 residue loop to an extra domain featuring a novel α‐helical fold. Molecular modelling and mutagenesis data implicate the loop in substrate binding and elucidate S1 and S2 subsites suitable to accommodate the side chains of the P1 glutamine and P2 leucine residues of Mpro substrates. Interactions involving the N‐terminus and the α‐helical domain stabilize the loop in the orientation required for trans‐cleavage activity. The study illustrates that RNA viruses have evolved unprecedented variations of the classical chymotrypsin fold.</div>
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