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- PDB-7zv5: Crystal structure of SARS Cov-2 main protease in complex with an ... -

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Basic information

Entry
Database: PDB / ID: 7zv5
TitleCrystal structure of SARS Cov-2 main protease in complex with an inhibitor 4
Components
  • 3C-like proteinase nsp5
  • inhibitor TRIP5
KeywordsANTIVIRAL PROTEIN / SARS Cov-2 / 3CL / main protease
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / snRNP Assembly / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / 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 toll-like receptor signaling pathway / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / SARS-CoV-2 modulates host translation machinery / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / host cell Golgi apparatus / symbiont-mediated suppression of host NF-kappaB cascade / 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 / single-stranded RNA binding / regulation of autophagy / viral protein processing / host cell perinuclear region of cytoplasm / lyase activity / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / copper ion binding / 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 / lipid binding / 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 / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. ...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 / : / Lipocalin signature. / 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 / 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 / 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. / : / :
Similarity search - Domain/homology
: / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.999 Å
AuthorsRahimova, R. / Di Micco, S. / Marquez, J.A.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European CommissionEuropean Union
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Rational design of the zonulin inhibitor AT1001 derivatives as potential anti SARS-CoV-2.
Authors: Di Micco, S. / Rahimova, R. / Sala, M. / Scala, M.C. / Vivenzio, G. / Musella, S. / Andrei, G. / Remans, K. / Mammri, L. / Snoeck, R. / Bifulco, G. / Di Matteo, F. / Vestuto, V. / Campiglia, ...Authors: Di Micco, S. / Rahimova, R. / Sala, M. / Scala, M.C. / Vivenzio, G. / Musella, S. / Andrei, G. / Remans, K. / Mammri, L. / Snoeck, R. / Bifulco, G. / Di Matteo, F. / Vestuto, V. / Campiglia, P. / Marquez, J.A. / Fasano, A.
History
DepositionMay 13, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 30, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 14, 2022Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.country ..._audit_author.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
B: inhibitor TRIP5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3524
Polymers34,1962
Non-polymers1562
Water2,504139
1
A: 3C-like proteinase nsp5
B: inhibitor TRIP5
hetero molecules

A: 3C-like proteinase nsp5
B: inhibitor TRIP5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,7048
Polymers68,3924
Non-polymers3134
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area5380 Å2
ΔGint-21 kcal/mol
Surface area25080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.753, 83.137, 54.828
Angle α, β, γ (deg.)90.000, 117.140, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein 3C-like proteinase nsp5 / 3CL-PRO / 3CLp / Main protease / Mpro / Non-structural protein 5 / nsp5 / SARS coronavirus main proteinase


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 (E. coli)
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Protein/peptide inhibitor TRIP5


Type: Peptide-like / Mass: 370.426 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: BIRD: PRD_002413
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Feature type: SUBJECT OF INVESTIGATION / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 139 / 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: 2.93 Å3/Da / Density % sol: 58.03 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Sodium nitrate, 0.1 M Bis-Tris propane pH 7.5 20 % (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.96546 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Dec 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96546 Å / Relative weight: 1
ReflectionResolution: 1.999→43.496 Å / Num. obs: 18153 / % possible obs: 82.2 % / Redundancy: 2.4 % / Biso Wilson estimate: 27.87 Å2 / CC1/2: 0.999 / Net I/σ(I): 14.4
Reflection shellResolution: 1.999→2.116 Å / Rmerge(I) obs: 0.518 / Num. unique obs: 910 / CC1/2: 0.816 / Rpim(I) all: 0.451 / Rrim(I) all: 0.69

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Processing

Software
NameVersionClassification
Aimlessdata scaling
BUSTER2.11.8 (20-OCT-2021)refinement
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5rgs

5rgs


Resolution: 1.999→19.3 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.904 / SU R Cruickshank DPI: 0.247 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.249 / SU Rfree Blow DPI: 0.198 / SU Rfree Cruickshank DPI: 0.199
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2398 879 4.84 %RANDOM
Rwork0.2014 ---
obs0.2031 18153 68.7 %-
Displacement parametersBiso max: 71.13 Å2 / Biso mean: 30.49 Å2 / Biso min: 10.9 Å2
Baniso -1Baniso -2Baniso -3
1-5.5726 Å20 Å2-2.7633 Å2
2---4.2625 Å20 Å2
3----1.3101 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: final / Resolution: 1.999→19.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2281 0 36 139 2456
Biso mean--34.71 30.94 -
Num. residues----301
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d782SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes420HARMONIC5
X-RAY DIFFRACTIONt_it2368HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion312SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1796SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2374HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3229HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion3.51
X-RAY DIFFRACTIONt_other_torsion15.81
LS refinement shellResolution: 2→2.06 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3434 21 4.96 %
Rwork0.2454 402 -
obs--22.2 %
Refinement TLS params.Method: refined / Origin x: -5.6244 Å / Origin y: -0.9477 Å / Origin z: 12.298 Å
111213212223313233
T-0.0229 Å2-0.0258 Å2-0.0401 Å2--0.1051 Å2-0.0127 Å2---0.0999 Å2
L0.9976 °20.4041 °2-0.014 °2-1.3291 °20.9627 °2--2.9975 °2
S0.0299 Å °-0.0577 Å °0.0262 Å °0.0475 Å °-0.0121 Å °-0.0582 Å °0.016 Å °-0.0441 Å °-0.0179 Å °
Refinement TLS groupSelection details: { A|* }

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