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- PDB-7tq7: Structure of MERS 3CL protease in complex with the cyclopropane b... -

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Basic information

Entry
Database: PDB / ID: 7tq7
TitleStructure of MERS 3CL protease in complex with the cyclopropane based inhibitor 13c
ComponentsOrf1a protein
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PROTEASE / severe acute respiratory syndrome coronavirus 2 / MERS 3CL protease Inhhibitors / hydrolase / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


host cell membrane / viral genome replication / methyltransferase activity / symbiont-mediated degradation of host mRNA / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / omega peptidase activity / methylation / symbiont-mediated perturbation of host ubiquitin-like protein modification / cysteine-type deubiquitinase activity ...host cell membrane / viral genome replication / methyltransferase activity / symbiont-mediated degradation of host mRNA / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / omega peptidase activity / methylation / symbiont-mediated perturbation of host ubiquitin-like protein modification / cysteine-type deubiquitinase activity / single-stranded RNA binding / host cell perinuclear region of cytoplasm / viral protein processing / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / cysteine-type endopeptidase activity / virus-mediated perturbation of host defense response / proteolysis / zinc ion binding / membrane
Similarity search - Function
Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / 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 ...Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / 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 / Betacoronavirus (BetaCoV) Nsp1 C-terminal 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 superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / : / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / Coronavirus 3Ecto domain profile. / : / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / NSP1, globular domain, alpha/betacoronavirus / : / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl 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. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp4 C-terminal (Nsp4C) domain profile. / Papain-like protease, thumb domain superfamily, coronavirus / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / Non-structural protein NSP7, coronavirus / Peptidase C30, coronavirus / Peptidase C16, coronavirus / Non-structural protein NSP9, 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 / 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 main protease (M-pro) domain profile. / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Macro domain / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / Macro domain-like / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-IRR / Orf1a protein
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. / Nguyen, H.N. / Chamandi, S.D. / Picard, H.R. / Madden, T.K. / Thruman, H.A. / 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)R01AI161085 United States
CitationJournal: Acs Pharmacol Transl Sci / Year: 2023
Title: Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies.
Authors: Dampalla, C.S. / Nguyen, H.N. / Rathnayake, A.D. / Kim, Y. / Perera, K.D. / Madden, T.K. / Thurman, H.A. / Machen, A.J. / Kashipathy, M.M. / Liu, L. / Battaile, K.P. / Lovell, S. / Chang, K.O. / Groutas, W.C.
History
DepositionJan 26, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 9, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 3, 2022Group: Database references / Structure summary / Category: citation / struct / Item: _citation.title / _struct.title
Revision 1.2Jan 11, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _citation_author.name
Revision 1.3Feb 1, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.4Oct 25, 2023Group: 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

Downloads & links

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Assembly

Deposited unit
A: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9183
Polymers34,3141
Non-polymers6042
Water3,693205
1
A: Orf1a protein
hetero molecules

A: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,8366
Polymers68,6282
Non-polymers1,2074
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area3700 Å2
ΔGint-5 kcal/mol
Surface area23380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.437, 57.940, 49.852
Angle α, β, γ (deg.)90.000, 112.370, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Orf1a protein


Mass: 34314.242 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Middle East respiratory syndrome-related coronavirus
Gene: orf1a / Plasmid: pET28 / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: A0A1L2E0X0
#2: Chemical ChemComp-IRR / N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-N~2~-({[(1R,2R)-2-propylcyclopropyl]methoxy}carbonyl)-L-leucinamide


Mass: 409.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H35N3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / 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: 1.97 Å3/Da / Density % sol: 37.69 %
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→49.29 Å / Num. obs: 29349 / % possible obs: 99.6 % / Redundancy: 3.5 % / Biso Wilson estimate: 21.6 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.06 / Net I/σ(I): 11.3 / Num. measured all: 101432
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Net I/σ(I) obs% possible all
1.7-1.733.10.669464514860.7181.897.3
9-49.293.30.0287292200.99832.999.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.7.7data scaling
PHASERphasing
PHENIX1.20rc2_4402refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WKK

5wkk


Resolution: 1.7→46.1 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.04 / Phase error: 20.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1902 1448 4.94 %
Rwork0.1593 27890 -
obs0.1609 29338 99.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 74.85 Å2 / Biso mean: 26.0312 Å2 / Biso min: 11.73 Å2
Refinement stepCycle: final / Resolution: 1.7→46.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2256 0 69 205 2530
Biso mean--30.12 33.7 -
Num. residues----302
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7-1.760.24751250.22022741286698
1.76-1.830.24211580.20822753291199
1.83-1.910.22341680.187727752943100
1.91-2.020.19461320.166528022934100
2.02-2.140.22171530.160527532906100
2.14-2.310.22081370.158228002937100
2.31-2.540.18651450.15328062951100
2.54-2.910.18011380.163827902928100
2.91-3.660.19821430.16112810295399
3.66-46.10.15841490.14112860300999

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