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- PDB-9att: Crystal structure of MERS 3CL protease in complex with a methylcy... -

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Basic information

Entry
Database: PDB / ID: 9att
TitleCrystal structure of MERS 3CL protease in complex with a methylcyclohexyl 2-pyrrolidone inhibitor (R-enantiomer)
Components3C-like proteinase nsp5
KeywordsHYDROLASE/INHIBITOR / MERS / 3CL protease inhibitors / COVID-19 / viral protein / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


host cell membrane / viral genome replication / methyltransferase activity / SARS coronavirus main proteinase / endonuclease activity / 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 ...host cell membrane / viral genome replication / methyltransferase activity / SARS coronavirus main proteinase / endonuclease activity / 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 / methylation / 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 / 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 / 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 / : ...Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / 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 / 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
Similarity search - Domain/homology
: / : / Replicase polyprotein 1a
Similarity search - Component
Biological speciesMiddle East respiratory syndrome-related coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsLiu, L. / Lovell, S. / Battaile, K.P. / Dampalla, C.S. / Groutas, W.C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI130092 United States
National Institutes of Health/Office of the DirectorS10OD030394 United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies.
Authors: Dampalla, C.S. / Kim, Y. / Zabiegala, A. / Howard, D.J. / Nguyen, H.N. / Madden, T.K. / Thurman, H.A. / Cooper, A. / Liu, L. / Battaile, K.P. / Lovell, S. / Chang, K.O. / Groutas, W.C.
History
DepositionFeb 27, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 6, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)70,9836
Polymers68,6282
Non-polymers2,3554
Water4,234235
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2040 Å2
ΔGint-7 kcal/mol
Surface area25440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.813, 106.234, 58.032
Angle α, β, γ (deg.)90.00, 108.98, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 34314.242 Da / Num. of mol.: 2 / Fragment: UNP residues 3248-3553
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Middle East respiratory syndrome-related coronavirus
Gene: 1a / Plasmid: pET-28 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: K9N638, SARS coronavirus main proteinase
#2: Chemical ChemComp-A1AGZ / (1S,2S)-2-{[N-({[(2R)-1-(cyclohexylmethyl)-5-oxopyrrolidin-2-yl]methoxy}carbonyl)-L-leucyl]amino}-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 588.714 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H44N4O9S
#3: Chemical ChemComp-A1AGY / (1R,2S)-2-{[N-({[(2R)-1-(cyclohexylmethyl)-5-oxopyrrolidin-2-yl]methoxy}carbonyl)-L-leucyl]amino}-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 588.714 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C26H44N4O9S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.12 Å3/Da / Density % sol: 41.86 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 10% w/v PEG3350, 100 mM HEPES, pH 7.5, 200 mM L-proline

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 19-ID / Wavelength: 0.9786 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: Jun 6, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.7→106.23 Å / Num. obs: 60625 / % possible obs: 96.8 % / Redundancy: 3.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.049 / Rpim(I) all: 0.029 / Rrim(I) all: 0.057 / Χ2: 0.97 / Net I/σ(I): 14.1 / Num. measured all: 223489
Reflection shellResolution: 1.7→1.74 Å / % possible obs: 99.9 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.782 / Num. measured all: 17144 / Num. unique obs: 4583 / CC1/2: 0.688 / Rpim(I) all: 0.47 / Rrim(I) all: 0.915 / Χ2: 0.99 / Net I/σ(I) obs: 1.9

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→24.77 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.01 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2104 2995 4.95 %
Rwork0.1735 --
obs0.1753 60562 96.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.7→24.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4663 0 144 235 5042
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075064
X-RAY DIFFRACTIONf_angle_d0.9386928
X-RAY DIFFRACTIONf_dihedral_angle_d15.2581887
X-RAY DIFFRACTIONf_chiral_restr0.061803
X-RAY DIFFRACTIONf_plane_restr0.006879
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.730.36671440.30092793X-RAY DIFFRACTION100
1.73-1.760.33541420.27862847X-RAY DIFFRACTION100
1.76-1.790.29741640.25642790X-RAY DIFFRACTION100
1.79-1.820.32051410.24542801X-RAY DIFFRACTION100
1.82-1.860.24451300.22622857X-RAY DIFFRACTION100
1.86-1.90.25861430.2012819X-RAY DIFFRACTION100
1.9-1.950.21961410.19682843X-RAY DIFFRACTION100
1.95-1.990.22421620.18642803X-RAY DIFFRACTION100
1.99-2.050.21981360.18272815X-RAY DIFFRACTION100
2.05-2.110.22551450.17832810X-RAY DIFFRACTION100
2.11-2.180.22251740.18112814X-RAY DIFFRACTION100
2.18-2.230.2149880.17611841X-RAY DIFFRACTION100
2.26-2.340.20021430.1842518X-RAY DIFFRACTION98
2.34-2.450.23991410.18692821X-RAY DIFFRACTION99
2.45-2.580.22051620.18092817X-RAY DIFFRACTION99
2.58-2.740.241170.19462404X-RAY DIFFRACTION85
2.74-2.950.23071490.18292789X-RAY DIFFRACTION98
2.95-3.250.1991560.18182789X-RAY DIFFRACTION99
3.25-3.720.1881380.16072843X-RAY DIFFRACTION100
3.72-4.680.16241540.13052843X-RAY DIFFRACTION100
4.68-24.770.18061250.14672910X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.7954-0.3335-0.0930.80950.20380.59070.10990.2199-0.0707-0.1598-0.090.0939-0.0207-0.007600.21530.0082-0.02040.2205-0.01010.18363.5932-25.4316-3.6754
20.99730.12920.30390.45330.25650.9412-0.0103-0.02320.04870.02-0.01920.0534-0.0676-0.05600.19980.0067-0.01130.1857-0.00580.1623.1242-20.1216.9704
31.4848-0.4627-0.12860.96460.12450.6455-0.0288-0.09480.09250.0788-0.0297-0.0411-0.05430.0521-00.21410.013-0.01450.1937-0.02910.17237.3857-14.046733.3408
41.0971-0.48430.07611.6037-0.36770.62-0.0268-0.0727-0.06040.01120.0049-0.04730.00880.0337-00.17990.00060.00760.16910.00580.1611-18.1276-31.933617.6687
51.29770.55920.05860.56110.29590.7812-0.09070.02840.2542-0.01670.02370.0594-0.1819-0.073100.2974-0.0003-0.04170.18190.00680.2671-21.9448-0.424911.3389
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -1 through 86 )
2X-RAY DIFFRACTION2chain 'A' and (resid 87 through 203 )
3X-RAY DIFFRACTION3chain 'A' and (resid 204 through 304 )
4X-RAY DIFFRACTION4chain 'B' and (resid -1 through 203 )
5X-RAY DIFFRACTION5chain 'B' and (resid 204 through 304 )

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