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- PDB-7t40: Structure of MERS 3CL protease in complex with inhibitor 10c -

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Basic information

Entry
Database: PDB / ID: 7t40
TitleStructure of MERS 3CL protease in complex with inhibitor 10c
Components3C-like proteinase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PROTEASE / MERS 3CL protease Inhhibitors / hydrolase / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


host cell membrane / viral genome replication / methyltransferase activity / endonuclease activity / SARS coronavirus main proteinase / methylation / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding ...host cell membrane / viral genome replication / methyltransferase activity / endonuclease activity / SARS coronavirus main proteinase / methylation / 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 / 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 / viral protein processing / host cell perinuclear region of cytoplasm / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / symbiont-mediated activation of host autophagy / viral translational frameshifting / cysteine-type endopeptidase activity / proteolysis / zinc ion binding / membrane
Similarity search - Function
Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Trypsin-like serine proteases / Thrombin, subunit H / 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 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Trypsin-like serine proteases / Thrombin, subunit H / 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 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 / Non-structural protein 3, X-domain-like / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain / 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-FV5 / Chem-FVE / Replicase polyprotein 1a
Similarity search - Component
Biological speciesMiddle East respiratory syndrome-related coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 Å
AuthorsLovell, S. / Liu, L. / Battaile, K.P. / Chamandi, S.D. / Kim, Y. / Groutas, W.C. / Chang, K.O.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI130092 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease.
Authors: Dampalla, C.S. / Rathnayake, A.D. / Galasiti Kankanamalage, A.C. / Kim, Y. / Perera, K.D. / Nguyen, H.N. / Miller, M.J. / Madden, T.K. / Picard, H.R. / Thurman, H.A. / Kashipathy, M.M. / ...Authors: Dampalla, C.S. / Rathnayake, A.D. / Galasiti Kankanamalage, A.C. / Kim, Y. / Perera, K.D. / Nguyen, H.N. / Miller, M.J. / Madden, T.K. / Picard, H.R. / Thurman, H.A. / Kashipathy, M.M. / Liu, L. / Battaile, K.P. / Lovell, S. / Chang, K.O. / Groutas, W.C.
History
DepositionDec 9, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 8, 2022Group: 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.title / _citation.year
Revision 1.2Jun 15, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Oct 23, 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

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Assembly

Deposited unit
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7024
Polymers34,3141
Non-polymers1,3883
Water4,179232
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,4048
Polymers68,6282
Non-polymers2,7756
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area3600 Å2
ΔGint-9 kcal/mol
Surface area23610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.605, 58.056, 49.899
Angle α, β, γ (deg.)90.00, 112.70, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-579-

HOH

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Components

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


Mass: 34314.242 Da / Num. of mol.: 1 / Fragment: Full Length
Source method: isolated from a genetically manipulated source
Details: N-terminal hexahistidine tag
Source: (gene. exp.) Middle East respiratory syndrome-related coronavirus (isolate United Kingdom/H123990006/2012)
Strain: isolate United Kingdom/H123990006/2012 / Gene: 1a / Plasmid: pET28 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: K9N638, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Chemical ChemComp-FV5 / (1R,2S)-1-hydroxy-2-{[N-({[7-(methanesulfonyl)-7-azaspiro[3.5]nonan-2-yl]oxy}carbonyl)-L-leucyl]amino}-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 596.715 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H40N4O10S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-FVE / (1S,2S)-1-hydroxy-2-{[N-({[7-(methanesulfonyl)-7-azaspiro[3.5]nonan-2-yl]oxy}carbonyl)-L-leucyl]amino}-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 596.715 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H40N4O10S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C8H18O5 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / 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: 1.98 Å3/Da / Density % sol: 37.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 17% (w/v) PEG 10000, 100 mM Bis-Tris, 100 mM ammonium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 29, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→46.87 Å / Num. obs: 29415 / % possible obs: 99.5 % / Redundancy: 3.4 % / Biso Wilson estimate: 21.28 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.065 / Net I/σ(I): 10.5 / Num. measured all: 100588 / Scaling rejects: 4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Net I/σ(I) obs% possible all
1.7-1.733.10.673471615400.7491.799.7
9-46.873.30.0277062160.99931.997.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.20RC2_4402refinement
XDSdata reduction
Aimless0.7.7data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WKK

5wkk


Resolution: 1.7→46.87 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.06 / Phase error: 20.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.195 1448 4.93 %
Rwork0.156 --
obs0.158 29401 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.28 Å2
Refinement stepCycle: LAST / Resolution: 1.7→46.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2263 0 80 232 2575
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.760.29691280.23042775X-RAY DIFFRACTION100
1.76-1.830.27281580.21362791X-RAY DIFFRACTION100
1.83-1.910.23361680.18322781X-RAY DIFFRACTION100
1.91-2.020.2021290.16652822X-RAY DIFFRACTION100
2.02-2.140.20971550.15642753X-RAY DIFFRACTION100
2.14-2.310.2171380.1492810X-RAY DIFFRACTION100
2.31-2.540.20461430.15152819X-RAY DIFFRACTION100
2.54-2.910.20731410.15882780X-RAY DIFFRACTION99
2.91-3.660.18161410.15162798X-RAY DIFFRACTION98
3.66-46.870.16051470.13912824X-RAY DIFFRACTION98

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