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- PDB-9atg: Crystal structure of MERS 3CL protease in complex with a 2,2-difl... -

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Basic information

Entry
Database: PDB / ID: 9atg
TitleCrystal structure of MERS 3CL protease in complex with a 2,2-difluoro-5-methylbenzo[1,3]dioxole 2-pyrrolidone inhibitor
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 / methylation ...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 / methylation / 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 / 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 / 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: 1.75 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 26, 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 1.2Oct 30, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6403
Polymers34,3141
Non-polymers1,3252
Water2,972165
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,2796
Polymers68,6282
Non-polymers2,6514
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area4150 Å2
ΔGint-15 kcal/mol
Surface area24570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.892, 57.642, 49.711
Angle α, β, γ (deg.)90.00, 112.28, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 34314.242 Da / Num. of mol.: 1 / 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-A1AGT / (1S,2S)-2-({N-[({(2S)-1-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methyl]-5-oxopyrrolidin-2-yl}methoxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 662.657 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H36F2N4O11S
#3: Chemical ChemComp-A1AGS / (1R,2S)-2-({N-[({(2S)-1-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methyl]-5-oxopyrrolidin-2-yl}methoxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 662.657 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C27H36F2N4O11S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 165 / 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: 36.89 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 25% w/v PEG3350, 100 mM Tris, pH 8.5, 200 mM magnesium chloride hexahydrate

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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: Dec 5, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.75→49.05 Å / Num. obs: 26092 / % possible obs: 97.8 % / Redundancy: 6.9 % / CC1/2: 0.997 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.045 / Rrim(I) all: 0.118 / Χ2: 1 / Net I/σ(I): 10.1 / Num. measured all: 179323
Reflection shellResolution: 1.75→1.78 Å / % possible obs: 96.4 % / Redundancy: 7.2 % / Rmerge(I) obs: 1.169 / Num. measured all: 9953 / Num. unique obs: 1391 / CC1/2: 0.687 / Rpim(I) all: 0.467 / Rrim(I) all: 1.26 / Χ2: 0.9 / Net I/σ(I) obs: 1.8

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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: 1.75→46 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.2 / Phase error: 20.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1987 1252 4.8 %
Rwork0.1528 --
obs0.155 26063 97.49 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.75→46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2325 0 82 165 2572
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012525
X-RAY DIFFRACTIONf_angle_d1.0953460
X-RAY DIFFRACTIONf_dihedral_angle_d13.962932
X-RAY DIFFRACTIONf_chiral_restr0.062391
X-RAY DIFFRACTIONf_plane_restr0.009455
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.820.32291290.23162709X-RAY DIFFRACTION96
1.82-1.90.28611420.2082718X-RAY DIFFRACTION97
1.9-20.221400.1662726X-RAY DIFFRACTION97
2-2.130.24451200.15182739X-RAY DIFFRACTION97
2.13-2.290.19711410.152744X-RAY DIFFRACTION97
2.29-2.520.20771400.152777X-RAY DIFFRACTION98
2.52-2.890.20341510.15762747X-RAY DIFFRACTION98
2.89-3.640.18281530.14662795X-RAY DIFFRACTION98
3.64-460.16941360.13892856X-RAY DIFFRACTION98
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)
10.45370.0419-0.26180.3707-0.06850.67850.0229-0.06440.00980.10450.0026-0.0634-0.04730.1714-00.2145-0.016-0.02210.2076-0.0140.19345.751639.050617.2306
20.3485-0.14950.07320.25020.03350.055-0.0007-0.15630.2224-0.0155-0.04940.1123-0.44540.2412-0.00240.3953-0.0604-0.04110.2654-0.03920.24467.165449.58720.2065
30.25860.0016-0.19250.64720.17321.1038-0.017-0.0558-0.00020.0987-0.00570.0182-0.01470.046-00.14630.0007-0.01710.1705-0.00840.1636-0.123834.095112.9879
40.03650.0795-0.08730.1316-0.00040.04440.1683-0.1-0.20590.3119-0.0579-0.33150.29350.0008-0.00020.3380.0026-0.02610.26030.01710.321.675521.946322.5075
50.4977-0.1093-0.16640.52360.14380.6037-0.0310.0146-0.16480.1925-0.08630.1830.3412-0.2305-0.02880.2451-0.09140.05130.1981-0.05210.2284-17.917511.44856.2997
60.23860.1382-0.22870.1197-0.06020.3005-0.07590.1242-0.01040.2024-0.062-0.07140.2150.1272-0.00130.21780.00210.01380.2317-0.02530.2119-10.236217.04610.0212
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -1 through 62 )
2X-RAY DIFFRACTION2chain 'A' and (resid 63 through 94 )
3X-RAY DIFFRACTION3chain 'A' and (resid 95 through 183 )
4X-RAY DIFFRACTION4chain 'A' and (resid 184 through 203 )
5X-RAY DIFFRACTION5chain 'A' and (resid 204 through 274 )
6X-RAY DIFFRACTION6chain 'A' and (resid 275 through 304 )

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