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- PDB-6xhl: Covalent complex of SARS-CoV main protease with N-[(2S)-1-({(2S,3... -

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Basic information

Entry
Database: PDB / ID: 6xhl
TitleCovalent complex of SARS-CoV main protease with N-[(2S)-1-({(2S,3S)-3,4-dihydroxy-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide
Components3C-like proteinase
KeywordsVIRAL PROTEIN / coronavirus protease 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 / Replication of the SARS-CoV-1 genome / K48-linked deubiquitinase activity / host cell endoplasmic reticulum / K63-linked deubiquitinase activity / SARS-CoV-1 modulates host translation machinery / viral genome replication ...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 / Replication of the SARS-CoV-1 genome / K48-linked deubiquitinase activity / host cell endoplasmic reticulum / K63-linked deubiquitinase activity / SARS-CoV-1 modulates host translation machinery / viral genome replication / methyltransferase activity / SARS-CoV-1 activates/modulates innate immune responses / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / endonuclease activity / host cell Golgi apparatus / methylation / symbiont-mediated perturbation of host ubiquitin-like protein modification / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / 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 / cysteine-type endopeptidase activity / RNA-directed RNA polymerase activity / proteolysis / zinc ion binding / identical protein binding / membrane
Similarity search - Function
Non-structural protein 3, SUD-N macrodomain, SARS-CoV / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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 ...Non-structural protein 3, SUD-N macrodomain, SARS-CoV / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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 / 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 / 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 / Coronavirus 3Ecto domain profile. / 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. / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Coronavirus main protease (M-pro) domain profile. / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, coronavirus / Non-structural protein NSP7, coronavirus / Non-structural protein NSP8, coronavirus / RNA synthesis protein NSP10, coronavirus / Non-structural protein NSP4, C-terminal, coronavirus / RNA synthesis protein NSP10 superfamily, coronavirus / Non-structural protein NSP9 superfamily, coronavirus / Non-structural protein NSP7 superfamily, coronavirus / Non-structural protein NSP8 superfamily, coronavirus / Non-structural protein NSP4, C-terminal superfamily, coronavirus / Papain-like protease, thumb domain superfamily, coronavirus / Peptidase C30, domain 3, coronavirus / Non-structural protein 6, coronavirus / Coronavirus replicase NSP3, C-terminal / Non-structural protein NSP4, N-terminal, coronavirus / Coronavirus endopeptidase C30 / Coronavirus papain-like peptidase / Coronavirus replicase NSP8 / Coronavirus RNA synthesis protein NSP10 / Coronavirus replicase NSP4, C-terminal / Coronavirus replicase NSP6 / Coronavirus replicase NSP4, N-terminal / Coronavirus replicase NSP3, C-terminal / Coronavirus replicase NSP9 / Trypsin-like serine proteases / Non-structural protein 3, X-domain-like / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain / Thrombin, subunit H / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-V2M / Replicase polyprotein 1a
Similarity search - Component
Biological speciesHuman SARS coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.471 Å
AuthorsGajiwala, K.S. / Ferre, R.A. / Ryan, K. / Stewart, A.E.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19.
Authors: Hoffman, R.L. / Kania, R.S. / Brothers, M.A. / Davies, J.F. / Ferre, R.A. / Gajiwala, K.S. / He, M. / Hogan, R.J. / Kozminski, K. / Li, L.Y. / Lockner, J.W. / Lou, J. / Marra, M.T. / ...Authors: Hoffman, R.L. / Kania, R.S. / Brothers, M.A. / Davies, J.F. / Ferre, R.A. / Gajiwala, K.S. / He, M. / Hogan, R.J. / Kozminski, K. / Li, L.Y. / Lockner, J.W. / Lou, J. / Marra, M.T. / Mitchell Jr., L.J. / Murray, B.W. / Nieman, J.A. / Noell, S. / Planken, S.P. / Rowe, T. / Ryan, K. / Smith 3rd, G.J. / Solowiej, J.E. / Steppan, C.M. / Taggart, B.
History
DepositionJun 19, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Refinement description / Category: citation / citation_author / software
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _software.name
Revision 1.2Nov 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 2.0Aug 3, 2022Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_entity_nonpoly / struct_conn
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_leaving_atom_flag
Revision 2.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase
B: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,8164
Polymers67,8672
Non-polymers9492
Water6,756375
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-6 kcal/mol
Surface area25590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.77, 98.49, 59.63
Angle α, β, γ (deg.)90, 108.31, 90
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein 3C-like proteinase


Mass: 33933.688 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: N-[(2S)-1-({(2S,3S)-3,4-dihydroxy-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide
Source: (gene. exp.) Human SARS coronavirus / Gene: 1a / Production host: Escherichia coli (E. coli)
References: UniProt: P0C6U8, SARS coronavirus main proteinase
#2: Chemical ChemComp-V2M / N-[(2S)-1-({(2S,3S)-3,4-dihydroxy-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide / N-[(2S)-1-({(2S)-4-hydroxy-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide, bound form


Mass: 474.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H34N4O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 375 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.31 Å3/Da / Density % sol: 46.74 %
Crystal growTemperature: 294 K / Method: vapor diffusion
Details: Precipitant: 10.0 %w/v (8.0 uL of stock 50.0 %w/v) PEG 6000; Buffer: 0.1 M (4.0 uL of stock 1.0 M) MES (pH 6.00); Additive: 0.0 %v/v (0.0 uL of stock 100.0 %v/v) Dimethyl sulfoxide; Additive: ...Details: Precipitant: 10.0 %w/v (8.0 uL of stock 50.0 %w/v) PEG 6000; Buffer: 0.1 M (4.0 uL of stock 1.0 M) MES (pH 6.00); Additive: 0.0 %v/v (0.0 uL of stock 100.0 %v/v) Dimethyl sulfoxide; Additive: 10.0 % w/v (5.0 uL of stock 80.0 % w/v) Glycerol

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Data collection

DiffractionMean temperature: 98 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 16, 2000
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.471→56.6 Å / Num. obs: 76744 / % possible obs: 74.2 % / Redundancy: 3.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.047 / Rpim(I) all: 0.03 / Rrim(I) all: 0.056 / Net I/σ(I): 12.6
Reflection shellResolution: 1.471→1.599 Å / Rmerge(I) obs: 0.598 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 3839 / CC1/2: 0.543 / Rpim(I) all: 0.488 / Rrim(I) all: 0.777

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata scaling
BUSTERphasing
autoPROCdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1UK3

1uk3


Resolution: 1.471→56.61 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.946 / SU R Cruickshank DPI: 0.099 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.1 / SU Rfree Blow DPI: 0.093 / SU Rfree Cruickshank DPI: 0.093
RfactorNum. reflection% reflectionSelection details
Rfree0.2229 3814 -RANDOM
Rwork0.2035 ---
obs0.2045 76744 74.2 %-
Displacement parametersBiso mean: 26.67 Å2
Baniso -1Baniso -2Baniso -3
1--0.3786 Å20 Å20.3313 Å2
2--0.0606 Å20 Å2
3---0.318 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.471→56.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4648 0 68 375 5091
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084860HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.986606HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1664SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes825HARMONIC5
X-RAY DIFFRACTIONt_it4860HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion635SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4377SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4
X-RAY DIFFRACTIONt_other_torsion14.82
LS refinement shellResolution: 1.471→1.55 Å
RfactorNum. reflection% reflection
Rfree0.2376 78 -
Rwork0.2098 --
obs--9.97 %

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