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- PDB-6w79: Structure of SARS-CoV main protease bound to potent broad-spectru... -

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Basic information

Entry
Database: PDB / ID: 6w79
TitleStructure of SARS-CoV main protease bound to potent broad-spectrum non-covalent inhibitor X77
ComponentsMain protease
KeywordsVIRAL PROTEIN/INHIBITOR / main protease / Mpro / 3C-like / 3CLpro / non-covalent / inhibitor / SARS / SARS-CoV / COVID-19 / X77 / broad-spectrum / coronavirus / drug / Structural Genomics / Center for Structural Genomics of Infectious Diseases / CSGID / VIRAL PROTEIN / VIRAL PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-1 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / K48-linked deubiquitinase activity / Replication of the SARS-CoV-1 genome / K63-linked deubiquitinase activity / host cell endoplasmic reticulum / viral transcription / SARS-CoV-1 modulates host translation machinery ...Assembly of the SARS-CoV-1 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / Transcription of SARS-CoV-1 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / K48-linked deubiquitinase activity / Replication of the SARS-CoV-1 genome / K63-linked deubiquitinase activity / host cell endoplasmic reticulum / viral transcription / SARS-CoV-1 modulates host translation machinery / Transferases; Transferring one-carbon groups; Methyltransferases / SARS-CoV-1 activates/modulates innate immune responses / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / endonuclease activity / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / host cell endosome / 3'-5'-RNA exonuclease activity / symbiont-mediated degradation of host mRNA / 5'-3' DNA helicase activity / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / mRNA guanylyltransferase activity / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / DNA helicase / symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host ubiquitin-like protein modification / host cell Golgi apparatus / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / cysteine-type deubiquitinase activity / ubiquitinyl hydrolase 1 / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / lyase activity / single-stranded RNA binding / viral protein processing / host cell perinuclear region of cytoplasm / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / viral translational frameshifting / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / ATP hydrolysis activity / proteolysis / zinc ion binding / ATP binding / identical protein binding
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 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) 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 14, betacoronavirus / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerization / Nonstructural protein 15, middle domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / : / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / NSP1 globular domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / Betacoronavirus single-stranded poly(A) binding domain / Betacoronavirus Nsp3c-M domain profile. / NSP1, globular domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain, betacoronavirus / Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus / Betacoronavirus replicase NSP1 / NSP1, C-terminal domain, betacoronavirus / Betacoronavirus (BetaCoV) Nsp1 C-terminal domain profile. / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / Betacoronavirus Nsp3c-C domain profile. / Betacoronavirus Nsp3e nucleic acid-binding (NAB) domain profile. / DPUP/SUD, C-terminal, betacoronavirus / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Papain-like viral protease, palm and finger domains, coronavirus / Papain-like protease, N-terminal domain superfamily, coronavirus / Coronavirus replicase NSP2, N-terminal / : / Coronavirus (CoV) Nsp2 middle domain profile. / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / Nonstructural protein 2, N-terminal domain, coronavirus / Non-structural protein 2, C-terminal domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Peptidase family C16 domain profile. / Coronavirus replicase NSP7 / : / :
Similarity search - Domain/homology
Chem-X77 / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSARS-COV-2 (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.46 Å
AuthorsMesecar, A.D. / StJohn, S. / Center for Structural Genomics of Infectious Diseases (CSGID)
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HHSN272201700060C United States
CitationJournal: To Be Published
Title: A taxonomically-driven approach to development of potent, broad-spectrum inhibitors of coronavirus main protease including SARS-CoV-2 (COVID-19)
Authors: Mesecar, A.D.
History
DepositionMar 18, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Main protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8055
Polymers33,8771
Non-polymers9284
Water10,142563
1
A: Main protease
hetero molecules

A: Main protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,61010
Polymers67,7532
Non-polymers1,8568
Water362
TypeNameSymmetry operationNumber
crystal symmetry operation1_554x,y,z-11
crystal symmetry operation2_555-x,y,-z1
Buried area3030 Å2
ΔGint-0 kcal/mol
Surface area27780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.881, 81.260, 53.455
Angle α, β, γ (deg.)90.000, 104.231, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11A-532-

HOH

21A-834-

HOH

31A-988-

HOH

41A-1021-

HOH

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Components

#1: Protein Main protease


Mass: 33876.637 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) SARS-COV-2 (virus) / Strain: COVID-19 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P0C6X7*PLUS
#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-X77 / N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide


Mass: 459.583 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 563 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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

Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 3 uL drops that were formed by adding 1 uL of purified SARS-3CLpro (10 mg/mL) that had been incubated for three hours with a 3 molar excess of the of compound X77, and 2 uL of reservoir ...Details: 3 uL drops that were formed by adding 1 uL of purified SARS-3CLpro (10 mg/mL) that had been incubated for three hours with a 3 molar excess of the of compound X77, and 2 uL of reservoir solution: 3 mM DTT, 50 mM MES pH 6.0, 40 mM KCl, 1% MPD, and 5% PEG-10K
Temp details: Cold room for crystals

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: Dry nitrogen stream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.978 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 17, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.46→100 Å / Num. obs: 77810 / % possible obs: 99.7 % / Redundancy: 4.9 % / Biso Wilson estimate: 18.31 Å2 / Rpim(I) all: 0.022 / Rrim(I) all: 0.049 / Χ2: 1.45 / Net I/σ(I): 41.3
Reflection shellResolution: 1.46→1.49 Å / Redundancy: 4.5 % / Mean I/σ(I) obs: 2.6 / Num. unique obs: 3875 / CC1/2: 0.908 / CC star: 0.976 / Rpim(I) all: 0.286 / Rrim(I) all: 0.62 / Χ2: 0.893 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MDS

4mds


Resolution: 1.46→32.28 Å / SU ML: 0.1299 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 19.8421 / Details: TLS parameters were included into the refinement.
RfactorNum. reflection% reflection
Rfree0.1773 2000 2.57 %
Rwork0.1564 --
obs0.157 77771 99.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 30.07 Å2
Refinement stepCycle: LAST / Resolution: 1.46→32.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2371 0 62 563 2996
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00542635
X-RAY DIFFRACTIONf_angle_d0.89783617
X-RAY DIFFRACTIONf_chiral_restr0.078406
X-RAY DIFFRACTIONf_plane_restr0.0056466
X-RAY DIFFRACTIONf_dihedral_angle_d19.2604991
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection Rwork% reflection obs (%)
1.46-1.50.27061400.2439532397.62
1.5-1.540.2493143100.2152537299.73
1.54-1.580.2441440.2058543299.91
1.58-1.630.22281410.192539299.96
1.63-1.690.21131450.1813545699.95
1.69-1.760.18131410.1697537799.91
1.76-1.840.18081440.1697545199.96
1.84-1.940.18641440.1676543399.89
1.94-2.060.19111420.1633542099.96
2.06-2.220.19561440.1583543199.96
2.22-2.440.19931430.1639542999.98
2.44-2.790.18891440.1637544899.98
2.79-3.520.15781440.1449546799.95
3.52-32.280.14421410.1315534096.36
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.08105390412-1.63959956673-0.9789399075291.529432744910.2309644903251.22075067873-0.02218203425210.0725409759416-0.2886972893820.00845760224618-0.03464066651390.04031939395160.1033513910720.07538427102260.04699894221450.1372824252170.0220708207258-0.007016936944590.106968748538-0.001409342967290.1830338472034.91113910824-37.157682997120.9994655935
25.32100521206-0.125072601389-1.20864847922.17211515893-0.7670539216481.246392326130.0409616668492-0.119702848316-0.3629979289-0.0151434455481-0.168323585644-0.08238602197730.09482396894280.2038703265480.1012613333830.1918538209610.07240420760240.007332399774740.171642070202-0.02464375706270.23174428166217.0567473176-43.140448936517.1348596542
31.95576380168-0.389517259128-0.4277927030083.05051883789-1.212245171091.396172007540.04490608320980.092623274428-0.1151503319830.034244436958-0.0731666699545-0.0908385492795-0.04216619403750.1099262296610.02224365029970.109759929320.0302042179404-0.01008942894850.142636498574-0.01668428222840.1337685157545.26219917086-27.358842770316.2009114178
42.59109841665-0.162818019055-0.3601565802561.89292337936-0.01978761348651.358156312350.1145739105950.2348387267050.171865224581-0.118790530189-0.07089587729850.057334921719-0.151519213704-0.165584327026-0.04144593465020.1586898894880.07204802741180.007418303700920.1861309162410.02395433694160.130700545917-14.1984219777-10.102697920810.4943275341
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 43 )
2X-RAY DIFFRACTION2chain 'A' and (resid 44 through 100 )
3X-RAY DIFFRACTION3chain 'A' and (resid 101 through 200 )
4X-RAY DIFFRACTION4chain 'A' and (resid 201 through 306 )

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