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- PDB-6w63: Structure of COVID-19 main protease bound to potent broad-spectru... -

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Basic information

Entry
Database: PDB / ID: 6w63
TitleStructure of COVID-19 main protease bound to potent broad-spectrum non-covalent inhibitor X77
Components3C-like proteinase
KeywordsVIRAL PROTEIN/INHIBITOR / COVID-19 / SARS / SARS-CoV-2 / SARS-CoV / main protease / 3C-like protease / 3CL protease / 3Clpro / Mpro / broad-spectrum / inhibitor / proteinase / non-covalent / reversible / Structural Genomics / Center for Structural Genomics of Infectious Diseases / CSGID / ANTIVIRAL PROTEIN / VIRAL PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs ...protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / TRAF3-dependent IRF activation pathway / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / snRNP Assembly / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / symbiont-mediated suppression of host NF-kappaB cascade / host cell endosome / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / mRNA (guanine-N7)-methyltransferase / omega peptidase activity / methyltransferase cap1 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / DNA helicase / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / host cell perinuclear region of cytoplasm / single-stranded RNA binding / host cell endoplasmic reticulum membrane / viral protein processing / lyase activity / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / copper ion binding / RNA-directed RNA polymerase / viral translational frameshifting / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / lipid binding / DNA-templated transcription / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
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 / : / : ...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 Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Coronavirus Nsp12 Interface domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) 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 / Nidovirus 2-O-methyltransferase / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Nidovirus 3'-5' exoribonuclease domain / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / 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 / : / Lipocalin signature. / DNA2/NAM7 helicase-like, C-terminal / AAA domain / 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 / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Trypsin-like serine proteases / Carbamoyl-phosphate synthase subdomain signature 2. / 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 / Betacoronavirus single-stranded poly(A) binding domain / 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 replicase NSP2, C-terminal / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp2 middle domain profile. / 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 / : / Coronavirus 3Ecto domain profile. / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / : / NSP3, first ubiquitin-like (Ubl) domain, coronavirus
Similarity search - Domain/homology
Chem-X77 / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsMesecar, A.D. / 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 16, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Source and taxonomy / Structure summary
Category: entity / entity_name_com ...entity / entity_name_com / entity_src_gen / struct_ref / struct_ref_seq
Item: _entity.pdbx_description / _entity.pdbx_ec ..._entity.pdbx_description / _entity.pdbx_ec / _entity_src_gen.gene_src_common_name / _entity_src_gen.gene_src_strain / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_scientific_name / _struct_ref.db_code / _struct_ref.db_name / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_db_accession
Revision 1.2Oct 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: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2852
Polymers33,8261
Non-polymers4601
Water5,062281
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,5704
Polymers67,6512
Non-polymers9192
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Buried area3160 Å2
ΔGint-15 kcal/mol
Surface area25040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.050, 63.840, 106.588
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z
Components on special symmetry positions
IDModelComponents
11A-543-

HOH

21A-699-

HOH

31A-713-

HOH

41A-769-

HOH

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Components

#1: Protein 3C-like proteinase / 3CL-PRO / 3CLp


Mass: 33825.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: 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
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 281 / 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

CrystalDensity Matthews: 2.27 Å3/Da / Density % sol: 45.71 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop
Details: 3 mM DTT, 1% MPD, 80mM KCl, 50 mM MES pH 6.0, 16% PEG 10k 2uL protein ( 125 uM 3CLpro, 25 mM HEPES pH 7.5, 2.5 mM DTT, 1% DMSO, 400 uM 077) + 1 uL reservoir
Temp details: Room temperature

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: 100 / 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: Feb 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 2.1→100 Å / Num. obs: 18549 / % possible obs: 99.3 % / Redundancy: 8.5 % / Biso Wilson estimate: 25.8 Å2 / CC1/2: 0.986 / CC star: 0.996 / Rpim(I) all: 0.061 / Rrim(I) all: 0.176 / Χ2: 1.5 / Net I/σ(I): 17.2
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 5.7 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 870 / CC1/2: 0.797 / CC star: 0.942 / Rpim(I) all: 0.237 / Χ2: 0.783 / % possible all: 94

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6LU7

6lu7


Resolution: 2.1→40.91 Å / SU ML: 0.2046 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.8569
RfactorNum. reflection% reflection
Rfree0.2214 1852 10.01 %
Rwork0.1499 --
obs0.1571 18507 99.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 33.57 Å2
Refinement stepCycle: LAST / Resolution: 2.1→40.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2358 0 34 281 2673
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01052448
X-RAY DIFFRACTIONf_angle_d1.09383329
X-RAY DIFFRACTIONf_chiral_restr0.0567372
X-RAY DIFFRACTIONf_plane_restr0.008431
X-RAY DIFFRACTIONf_dihedral_angle_d15.08391424
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.160.24361330.18541195X-RAY DIFFRACTION94.12
2.16-2.220.26541370.16851234X-RAY DIFFRACTION97.86
2.22-2.290.24171410.15811265X-RAY DIFFRACTION99.58
2.29-2.370.24611400.15881274X-RAY DIFFRACTION99.93
2.37-2.470.22861410.15551259X-RAY DIFFRACTION100
2.47-2.580.24971410.15981278X-RAY DIFFRACTION100
2.58-2.720.25161410.17131262X-RAY DIFFRACTION99.86
2.72-2.890.33221450.17371300X-RAY DIFFRACTION100
2.89-3.110.23081410.16461278X-RAY DIFFRACTION99.86
3.11-3.420.23161440.15321298X-RAY DIFFRACTION99.86
3.42-3.920.19511440.13331297X-RAY DIFFRACTION99.59
3.92-4.930.1571470.11391322X-RAY DIFFRACTION99.46
4.93-40.910.20621570.15171393X-RAY DIFFRACTION98.98
Refinement TLS params.Method: refined / Origin x: -2.2956889213 Å / Origin y: 18.9092186008 Å / Origin z: -26.0226539739 Å
111213212223313233
T0.12523807745 Å2-0.000513229276641 Å20.0105009829753 Å2-0.121505526194 Å2-0.00182276376289 Å2--0.131035247225 Å2
L0.51202262118 °20.0651472751098 °20.438972847717 °2-0.105268538296 °2-0.014544524504 °2--0.432964208946 °2
S-0.0185130029258 Å °0.000107245518397 Å °-0.0444698077546 Å °-0.00607398761875 Å °0.017831171902 Å °0.0150361523707 Å °0.0328493246714 Å °-0.00250612683581 Å °6.56422809364E-5 Å °
Refinement TLS groupSelection details: all

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