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- PDB-7tq8: Structure of MERS 3CL protease in complex with the cyclopropane b... -

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Basic information

Entry
Database: PDB / ID: 7tq8
TitleStructure of MERS 3CL protease in complex with the cyclopropane based inhibitor 14d
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 / endonuclease activity / symbiont-mediated degradation of host mRNA / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / methylation / omega peptidase activity / symbiont-mediated perturbation of host ubiquitin-like protein modification ...host cell membrane / viral genome replication / methyltransferase activity / endonuclease activity / symbiont-mediated degradation of host mRNA / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / methylation / omega peptidase activity / symbiont-mediated perturbation of host ubiquitin-like protein modification / cysteine-type deubiquitinase activity / single-stranded RNA binding / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / 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 / 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 / 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 / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Trypsin-like serine proteases / 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 / Thrombin, subunit H / 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-IRK / Chem-IUB / Orf1a protein
Similarity search - Component
Biological speciesMiddle East respiratory syndrome-related coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsLiu, L. / Lovell, S. / 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 1.0Mar 2, 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
Revision 1.5Nov 20, 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: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4924
Polymers34,3141
Non-polymers1,1773
Water4,071226
1
A: Orf1a protein
hetero molecules

A: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,9838
Polymers68,6282
Non-polymers2,3556
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area3810 Å2
ΔGint-7 kcal/mol
Surface area23020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.729, 57.611, 49.742
Angle α, β, γ (deg.)90.00, 112.22, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-709-

HOH

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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-IRK / (1R,2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-2-{[N-({[(1R,2S)-2-propylcyclopropyl]methoxy}carbonyl)-L-leucyl]amino}propane-1-sulfonic acid


Mass: 491.599 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H37N3O8S
#3: Chemical ChemComp-IUB / (1S,2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-2-{[N-({[(1R,2S)-2-propylcyclopropyl]methoxy}carbonyl)-L-leucyl]amino}propane-1-sulfonic acid


Mass: 491.599 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H37N3O8S
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 226 / 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: 1.95 Å3/Da / Density % sol: 36.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 25% (w/v) PEG 3350, 100 mM Tris, 200 mM Lithium Sulfate

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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: 1.65→49.01 Å / Num. obs: 31177 / % possible obs: 98.2 % / Redundancy: 5.2 % / Biso Wilson estimate: 21.12 Å2 / Rmerge(I) obs: 0.085 / Net I/σ(I): 10.1
Reflection shellResolution: 1.65→1.68 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.777 / Num. unique obs: 1431 / % possible all: 94

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Processing

Software
NameVersionClassification
PHENIXDEV_4302refinement
XDSdata reduction
Aimless0.7.7data scaling
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WKK

5wkk


Resolution: 1.65→46.05 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.02 / Phase error: 20.2 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.191 1566 5.03 %
Rwork0.159 --
obs0.16 31153 98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.81 Å2
Refinement stepCycle: LAST / Resolution: 1.65→46.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2249 0 71 226 2546
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.70.27131430.20342563X-RAY DIFFRACTION95
1.7-1.760.22751280.17682703X-RAY DIFFRACTION98
1.76-1.840.22161290.17622721X-RAY DIFFRACTION99
1.84-1.920.22261440.16942545X-RAY DIFFRACTION97
1.92-2.020.21470.15322611X-RAY DIFFRACTION98
2.02-2.150.1881360.14912749X-RAY DIFFRACTION99
2.15-2.310.18881350.14822727X-RAY DIFFRACTION100
2.31-2.540.21831460.15372728X-RAY DIFFRACTION100
2.55-2.910.19251680.16082729X-RAY DIFFRACTION100
2.91-3.670.19521370.16272742X-RAY DIFFRACTION99
3.67-46.050.16141530.15342769X-RAY DIFFRACTION98

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