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- PDB-2amq: Crystal Structure Of SARS_CoV Mpro in Complex with an Inhibitor N3 -

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Entry
Database: PDB / ID: 2amq
TitleCrystal Structure Of SARS_CoV Mpro in Complex with an Inhibitor N3
Components
  • 3C-like proteinase
  • N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE
KeywordsHYDROLASE / ANTI-PARALLEL B-BARREL / ANTI-PARALLEL A-HELICES
Function / homology
Function and homology information


positive regulation of ubiquitin-specific protease activity / Maturation of replicase proteins / Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-1 sgRNAs / Lys48-specific deubiquitinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / 7-methylguanosine mRNA capping / mRNA (guanine-N7-)-methyltransferase activity / Transferases; Transferring one-carbon groups; Methyltransferases ...positive regulation of ubiquitin-specific protease activity / Maturation of replicase proteins / Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Transcription of SARS-CoV-1 sgRNAs / Lys48-specific deubiquitinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-1 genome / 7-methylguanosine mRNA capping / mRNA (guanine-N7-)-methyltransferase activity / Transferases; Transferring one-carbon groups; Methyltransferases / 5'-3' RNA helicase activity / RNA phosphodiester bond hydrolysis, exonucleolytic / Lyases; Phosphorus-oxygen lyases / modulation by virus of host autophagy / mRNA methylation / double membrane vesicle viral factory outer membrane / suppression by virus of host translation / ISG15-specific protease activity / suppression by virus of host type I interferon production / SARS coronavirus main proteinase / induction by virus of catabolism of host mRNA / cytoplasmic viral factory / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / 3'-5'-exoribonuclease activity / G-quadruplex RNA binding / suppression by virus of host ISG15-protein conjugation / host cell endoplasmic reticulum-Golgi intermediate compartment / protein K48-linked deubiquitination / suppression by virus of host toll-like receptor signaling pathway / suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / transcription, RNA-templated / suppression by virus of host NF-kappaB cascade / viral transcription / modulation by virus of host protein ubiquitination / protein K63-linked deubiquitination / methyltransferase cap1 / positive stranded viral RNA replication / protein autoprocessing / viral genome replication / mRNA (nucleoside-2'-O-)-methyltransferase activity / suppression by virus of host TRAF activity / helicase activity / ubiquitinyl hydrolase 1 / double-stranded RNA binding / DNA helicase / thiol-dependent deubiquitinase / DNA helicase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell perinuclear region of cytoplasm / viral protein processing / RNA helicase / induction by virus of host autophagy / endonuclease activity / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / suppression by virus of host type I interferon-mediated signaling pathway / transcription, DNA-templated / host cell cytoplasm / protein dimerization activity / : / endoplasmic reticulum membrane / zinc ion binding / integral component of membrane / ATP binding / identical protein binding / cytosol
Similarity search - Function
Non-structural protein 3, SUD-N macrodomain, SARS-CoV / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. ...Non-structural protein 3, SUD-N macrodomain, SARS-CoV / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 14, betacoronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Viral (Superfamily 1) RNA helicase / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, N-terminal oligomerisation / Coronavirus replicase NSP15, N-terminal oligomerisation / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus replicase NSP15, middle domain / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, middle domain / Coronavirus RNA-dependent RNA polymerase, N-terminal / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronaviridae zinc-binding (CV ZBD) domain profile. / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP1 superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, coronavirus / Betacoronavirus replicase NSP3, N-terminal / Non-structural protein 2, SARS-CoV-like / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / NendoU domain, nidovirus / Endoribonuclease EndoU-like / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Betacoronavirus Nsp3c-M domain profile. / Non-structural protein NSP1, betacoronavirus / Betacoronavirus single-stranded poly(A) binding domain / Betacoronavirus replicase NSP1 / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / Betacoronavirus Nsp3c-C domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein 6, betacoronavirus / Replicase polyprotein, nucleic acid-binding domain superfamily / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp8 cofactor domain profile. / Coronavirus Nsp9 single-stranded RNA (ssRNA)-binding domain profile. / Coronavirus (CoV) ExoN/MTase coactivator domain profile. / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus Nsp3d Ubl domain profile. / Coronavirus Nsp3a Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Coronavirus replicase NSP7 / Coronavirus endopeptidase C30 / Coronavirus replicase NSP3, C-terminal / Coronavirus papain-like peptidase / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus main protease (M-pro) domain profile. / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP4, N-terminal / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein 6, coronavirus / Peptidase C30, domain 3, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP8, coronavirus-like / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus
Similarity search - Domain/homology
N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE / Replicase polyprotein 1ab / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSARS coronavirus
synthetic construct (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsYang, H. / Xue, X. / Yang, K. / Zhao, Q. / Bartlam, M. / Rao, Z.
CitationJournal: Plos Biol. / Year: 2005
Title: Design of Wide-Spectrum Inhibitors Targeting Coronavirus Main Proteases.
Authors: Yang, H. / Xie, W. / Xue, X. / Yang, K. / Ma, J. / Liang, W. / Zhao, Q. / Zhou, Z. / Pei, D. / Ziebuhr, J. / Hilgenfeld, R. / Yuen, K.Y. / Wong, L. / Gao, G. / Chen, S. / Chen, Z. / Ma, D. / ...Authors: Yang, H. / Xie, W. / Xue, X. / Yang, K. / Ma, J. / Liang, W. / Zhao, Q. / Zhou, Z. / Pei, D. / Ziebuhr, J. / Hilgenfeld, R. / Yuen, K.Y. / Wong, L. / Gao, G. / Chen, S. / Chen, Z. / Ma, D. / Bartlam, M. / Rao, Z.
History
DepositionAug 10, 2005Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Sep 13, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 9, 2015Group: Structure summary

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3C-like proteinase
B: 3C-like proteinase
C: N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE
D: N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE


Theoretical massNumber of molelcules
Total (without water)69,9384
Polymers69,9384
Non-polymers00
Water5,873326
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5020 Å2
ΔGint-28 kcal/mol
Surface area25150 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)52.061, 95.704, 67.587
Angle α, β, γ (deg.)90.00, 102.88, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein 3C-like proteinase / sars main protease / 3CL-PRO


Mass: 34288.086 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) SARS coronavirus / Genus: Coronavirus / Plasmid: PGEX-6P-1 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P59641, UniProt: P0C6X7*PLUS, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein/peptide N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE


Type: Peptide-like / Class: Inhibitor / Mass: 680.791 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
References: N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 326 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.5 Å3/Da / Density % sol: 49.5 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6
Details: PEG 6000, MES, DMSO, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jul 13, 2004
RadiationMonochromator: osmic mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 28372 / Num. obs: 28372 / % possible obs: 98 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1
Reflection shellResolution: 2.3→2.34 Å / % possible all: 96

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Processing

Software
NameClassification
HKL-2000data collection
SCALEPACKdata scaling
CNSrefinement
HKL-2000data reduction
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→50 Å / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.23 1320 random
Rwork0.194 --
all0.23 28482 -
obs0.216 27091 -
Refinement stepCycle: LAST / Resolution: 2.3→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4785 0 0 326 5111
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.016
X-RAY DIFFRACTIONc_angle_deg1.97

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