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Entry
Database: PDB / ID: 6fv2
TitleStructure of human coronavirus NL63 main protease in complex with the alpha-ketoamide (S)-N-benzyl-3-((S)-2-cinnamamido-3-phenylpropanamido)-2-oxo-4-((S)-2-oxopyrrolidin-3-yl)butanamide (cinnamoyl-phenylalanine-GlnLactam-CO-CO-NH-benzyl)
Components3C-like proteinase
KeywordsHYDROLASE / Viral protease / coronavirus / alpha-ketoamide / inhibitor
Function / homology
Function and homology information


host cell membrane / Lyases; Phosphorus-oxygen lyases / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / endonuclease activity / mRNA guanylyltransferase / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity ...host cell membrane / Lyases; Phosphorus-oxygen lyases / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / endonuclease activity / mRNA guanylyltransferase / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / methyltransferase cap1 / symbiont-mediated perturbation of host ubiquitin-like protein modification / DNA helicase / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / RNA helicase activity / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / RNA helicase / 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 / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / : / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain / Pectin lyase fold/virulence factor / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 ...Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / : / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain / Pectin lyase fold/virulence factor / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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. / Trypsin-like serine proteases / 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
Similarity search - Domain/homology
Chem-D03 / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesHuman coronavirus NL63
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsZhang, L. / Hilgenfeld, R.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Center for Infection Research (DZIF)TTU 01.803 Germany
CitationJournal: J.Med.Chem. / Year: 2020
Title: Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication Structure-based design, synthesis, and activity assessment.
Authors: Zhang, L. / Lin, D. / Kusov, Y. / Nian, Y. / Ma, Q. / Wang, J. / von Brunn, A. / Leyssen, P. / Lanko, K. / Neyts, J. / de Wilde, A.H. / Snijder, E.J. / Liu, H. / Hilgenfeld, R.
History
DepositionFeb 28, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Apr 28, 2021Group: Source and taxonomy / Structure summary / Category: entity / entity_name_com / entity_src_gen
Item: _entity.pdbx_description / _entity.pdbx_ec ..._entity.pdbx_description / _entity.pdbx_ec / _entity_name_com.name / _entity_src_gen.gene_src_common_name
Revision 1.3May 1, 2024Group: 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.4Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
C: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,6209
Polymers99,6383
Non-polymers1,9826
Water4,306239
1
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8733
Polymers33,2131
Non-polymers6612
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8733
Polymers33,2131
Non-polymers6612
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8733
Polymers33,2131
Non-polymers6612
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)131.115, 211.044, 115.630
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11B-569-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13B
23C

NCS domain segments:

Component-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / Refine code: 1

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11TYRTYRAA1 - 2981 - 298
21TYRTYRBB1 - 2981 - 298
12TYRTYRAA1 - 2981 - 298
22TYRTYRCC1 - 2981 - 298
13GLYGLYBB1 - 2991 - 299
23GLYGLYCC1 - 2991 - 299

NCS ensembles :
ID
1
2
3

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.585725, 0.69513, 0.416798), (-0.722918, -0.21553, -0.656457), (-0.36649, -0.685815, 0.628763)60.16, 59.25474, 78.16822

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Components

#1: Protein 3C-like proteinase / 3CL-PRO / 3CLp / M-PRO / nsp5 / p34


Mass: 33212.566 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human coronavirus NL63 / Gene: rep, 1a-1b / Production host: Escherichia coli (E. coli)
References: UniProt: P0C6X5, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-D03 / (S)-N-benzyl-3-((S)-2-cinnamamido-3-phenylpropanamido)-2-oxo-4-((S)-2-oxopyrrolidin-3-yl)butanamide


Mass: 568.663 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C33H36N4O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 239 / Source method: isolated from a natural source / Formula: H2O
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: 4.01 Å3/Da / Density % sol: 69.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.1 M lithium sulfate monohydrate, 0.1 M sodium citrate tribasic dihydrate, 25% PEG 1,000, pH 6.0.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Nov 21, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.95→48 Å / Num. obs: 33470 / % possible obs: 98.1 % / Redundancy: 5.6 % / CC1/2: 0.994 / Rmerge(I) obs: 0.112 / Rpim(I) all: 0.051 / Rrim(I) all: 0.123 / Net I/σ(I): 13.1
Reflection shellResolution: 2.95→3.11 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.569 / Num. unique obs: 4925 / CC1/2: 0.808 / Rpim(I) all: 0.259 / Rrim(I) all: 0.627 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Structure of human coronavirus NL63 main protease

Resolution: 2.95→48 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.869 / SU B: 14.809 / SU ML: 0.264 / Cross valid method: THROUGHOUT / ESU R: 1.155 / ESU R Free: 0.367 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24829 1609 5 %RANDOM
Rwork0.19666 ---
obs0.19931 30731 94.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 56.105 Å2
Baniso -1Baniso -2Baniso -3
1-2.08 Å20 Å20 Å2
2---1.77 Å20 Å2
3----0.31 Å2
Refinement stepCycle: 1 / Resolution: 2.95→48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6813 0 144 239 7196
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0197119
X-RAY DIFFRACTIONr_bond_other_d0.0040.026370
X-RAY DIFFRACTIONr_angle_refined_deg1.81.9519654
X-RAY DIFFRACTIONr_angle_other_deg1.126314745
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5025896
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.1624295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.842151079
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.4961527
X-RAY DIFFRACTIONr_chiral_restr0.0940.21086
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.028055
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021544
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.5215.4853593
X-RAY DIFFRACTIONr_mcbond_other4.5215.4853592
X-RAY DIFFRACTIONr_mcangle_it7.1948.2214486
X-RAY DIFFRACTIONr_mcangle_other7.1938.2214487
X-RAY DIFFRACTIONr_scbond_it5.0596.0443526
X-RAY DIFFRACTIONr_scbond_other5.0586.0453527
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.8858.8835169
X-RAY DIFFRACTIONr_long_range_B_refined1266.2198000
X-RAY DIFFRACTIONr_long_range_B_other11.99966.2198001
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Auth asym-ID: A / Refine-ID: X-RAY DIFFRACTION / Type: tight thermal / Weight position: 0.71

Ens-IDDom-IDNumberRms dev position (Å)
11226210.2
2222628.04
3322668.49
LS refinement shellResolution: 2.95→3.027 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.37 113 -
Rwork0.332 2379 -
obs--99.52 %

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