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

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Basic information

Entry
Database: PDB / ID: 9ati
TitleCrystal structure of MERS 3CL protease in complex with a racemic bicyclo[2.2.1]heptenyl-methyl 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 / 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: 1.6 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 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,5123
Polymers34,3141
Non-polymers1,1972
Water3,927218
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,0236
Polymers68,6282
Non-polymers2,3954
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area3880 Å2
ΔGint-20 kcal/mol
Surface area24860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.309, 58.122, 49.755
Angle α, β, γ (deg.)90.00, 112.18, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-624-

HOH

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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-A1AGV / (1S,2S)-2-{[N-({[(3S)-1-{[(1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-yl]methyl}-5-oxopyrrolidin-3-yl]methoxy}carbonyl)-L-leucyl]amino}-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 598.709 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C27H42N4O9S
#3: Chemical ChemComp-A1AGU / (1R,2S)-2-{[N-({[(3S)-1-{[(1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-yl]methyl}-5-oxopyrrolidin-3-yl]methoxy}carbonyl)-L-leucyl]amino}-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 598.709 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C27H42N4O9S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 218 / 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: 37.77 %
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 ammonium acetate

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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: 1.6→49.41 Å / Num. obs: 35346 / % possible obs: 99.9 % / Redundancy: 5.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.041 / Rrim(I) all: 0.097 / Χ2: 0.96 / Net I/σ(I): 10.1 / Num. measured all: 196170
Reflection shellResolution: 1.6→1.63 Å / % possible obs: 100 % / Redundancy: 5.8 % / Rmerge(I) obs: 0.937 / Num. measured all: 10190 / Num. unique obs: 1747 / CC1/2: 0.633 / Rpim(I) all: 0.416 / Rrim(I) all: 1.028 / Χ2: 0.95 / 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: 1.6→46.91 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.03 / Phase error: 20.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1955 1796 5.08 %
Rwork0.1558 --
obs0.1578 35330 99.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.6→46.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2318 0 74 218 2610
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092525
X-RAY DIFFRACTIONf_angle_d0.983459
X-RAY DIFFRACTIONf_dihedral_angle_d14.215931
X-RAY DIFFRACTIONf_chiral_restr0.059400
X-RAY DIFFRACTIONf_plane_restr0.008437
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.640.27751330.23942552X-RAY DIFFRACTION100
1.64-1.690.24371280.21162566X-RAY DIFFRACTION100
1.69-1.750.24431470.19582578X-RAY DIFFRACTION100
1.75-1.810.21671300.18882581X-RAY DIFFRACTION100
1.81-1.880.26231330.17422584X-RAY DIFFRACTION100
1.88-1.970.20481560.16332536X-RAY DIFFRACTION100
1.97-2.070.18371400.14952585X-RAY DIFFRACTION100
2.07-2.20.20291300.15142574X-RAY DIFFRACTION100
2.2-2.370.21161500.15512566X-RAY DIFFRACTION100
2.37-2.610.21241410.15822592X-RAY DIFFRACTION100
2.61-2.990.18951480.15692569X-RAY DIFFRACTION100
2.99-3.760.15851340.14472594X-RAY DIFFRACTION99
3.76-46.910.18161260.13952657X-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)
11.0382-0.50910.15391.993-0.08711.2273-0.01750.058-0.0667-0.11790.0073-0.02920.03350.00890.01650.1322-0.0079-0.00230.14790.0040.1306-9.70271.80938.0798
21.9211-0.30.1391.98140.45392.53760.0098-0.0693-0.2278-0.0808-0.0429-0.0820.30610.05390.03580.16380.0270.01540.14060.03480.17386.1285-17.137918.3442
31.2427-0.42760.45391.1326-0.69271.70810.04950.09220.0019-0.11730.02950.12040.0539-0.1174-0.1040.1333-0.0066-0.00670.15750.0020.1557-15.30219.15096.0168
43.299-0.7404-1.09493.9226-0.46982.17710.0546-0.03190.31290.24160.0328-0.0225-0.3878-0.1094-0.08430.21810.0132-0.04750.18460.02330.179-16.584219.76022.6163
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 95 through 203 )
2X-RAY DIFFRACTION2chain 'A' and (resid 204 through 303 )
3X-RAY DIFFRACTION3chain 'A' and (resid -1 through 62 )
4X-RAY DIFFRACTION4chain 'A' and (resid 63 through 94 )

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