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Basic information

Entry
Database: PDB / ID: 9ate
TitleCrystal structure of MERS 3CL protease in complex with a methylbicyclo[2.2.1]heptane 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: 1.85 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
B: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,0316
Polymers68,6282
Non-polymers2,4034
Water3,639202
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3080 Å2
ΔGint-4 kcal/mol
Surface area25590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.847, 105.869, 57.751
Angle α, β, γ (deg.)90.00, 109.08, 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-A1AGN / (1S,2S)-2-{[N-({[(2S)-1-{[(1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl]methyl}-5-oxopyrrolidin-2-yl]methoxy}carbonyl)-L-leucyl]amino}-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 600.725 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H44N4O9S
#3: Chemical ChemComp-A1AGM / (1R,2S)-2-{[N-({[(2S)-1-{[(1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl]methyl}-5-oxopyrrolidin-2-yl]methoxy}carbonyl)-L-leucyl]amino}-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 600.725 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C27H44N4O9S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 202 / 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: 2.1 Å3/Da / Density % sol: 41.38 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 25% w/v PEG3350, 100 mM HEPES, pH 7.5

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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: 1.85→105.87 Å / Num. obs: 48244 / % possible obs: 100 % / Redundancy: 6.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.03 / Rrim(I) all: 0.078 / Χ2: 1.02 / Net I/σ(I): 13.7 / Num. measured all: 331595
Reflection shellResolution: 1.85→1.9 Å / % possible obs: 99.9 % / Redundancy: 6.7 % / Rmerge(I) obs: 1.062 / Num. measured all: 23552 / Num. unique obs: 3519 / CC1/2: 0.679 / Rpim(I) all: 0.442 / Rrim(I) all: 1.152 / Χ2: 1.09 / Net I/σ(I) obs: 2

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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: 1.85→54.58 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.1 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1913 2343 4.86 %
Rwork0.1632 --
obs0.1646 48194 99.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.85→54.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4637 0 148 202 4987
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075099
X-RAY DIFFRACTIONf_angle_d0.9766993
X-RAY DIFFRACTIONf_dihedral_angle_d15.431870
X-RAY DIFFRACTIONf_chiral_restr0.06807
X-RAY DIFFRACTIONf_plane_restr0.007888
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.890.26661510.23952665X-RAY DIFFRACTION100
1.89-1.930.27431360.22792678X-RAY DIFFRACTION100
1.93-1.970.26651360.20692678X-RAY DIFFRACTION100
1.97-2.020.22061420.18492699X-RAY DIFFRACTION100
2.02-2.080.23811330.17962704X-RAY DIFFRACTION100
2.08-2.140.18771280.16892690X-RAY DIFFRACTION100
2.14-2.210.24161270.17062700X-RAY DIFFRACTION100
2.21-2.290.23641330.17172692X-RAY DIFFRACTION100
2.29-2.380.22871480.17532706X-RAY DIFFRACTION100
2.38-2.490.211510.17222689X-RAY DIFFRACTION100
2.49-2.620.20791390.16972709X-RAY DIFFRACTION100
2.62-2.780.24371250.18542682X-RAY DIFFRACTION100
2.78-30.21361470.1752700X-RAY DIFFRACTION100
3-3.30.18781240.17532712X-RAY DIFFRACTION100
3.3-3.780.17641440.15182701X-RAY DIFFRACTION100
3.78-4.760.14641300.13372714X-RAY DIFFRACTION100
4.76-54.580.16431490.15022732X-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)
12.05021.47890.49983.250.73930.8039-0.00920.06-0.2770.0134-0.0138-0.02560.1403-0.00490.01680.2842-0.00790.05320.2468-0.02630.2878.4163-38.575110.2294
21.99650.2384-0.25272.71640.10121.40990.01880.09590.0687-0.0607-0.00190.145-0.0162-0.0589-0.02220.1965-0.0083-0.00150.1984-0.00460.19658.786-25.76449.8866
32.7943-0.8020.67172.1463-0.25131.7096-0.0512-0.09470.40330.1140.0220.0358-0.17510.0410.03530.3013-0.01260.01050.2495-0.00830.408412.3482-0.195915.957
42.48490.11730.74390.9111-0.48761.70280.0928-0.2677-0.01880.137-0.1082-0.1208-0.12290.18190.03950.2591-0.03010.0010.28640.00640.2226-13.272-23.176328.5725
51.75910.71920.28761.37650.24680.07720.2208-0.423-0.28540.3331-0.1585-0.11120.1710.0044-0.06310.3852-0.0358-0.06940.4240.10430.29-10.7964-30.742536.1143
61.92520.02780.29071.7822-0.98361.64770.0398-0.0693-0.01750.001-0.039-0.09480.06570.0396-0.00070.2468-0.008-0.00920.25710.01370.2241-15.1313-22.315320.3381
70.31370.3459-0.13680.9764-0.35021.8410.0249-0.09840.24080.3504-0.06850.0232-0.7930.19720.02620.4948-0.0213-0.01660.3910.03390.3618-6.7704-9.080219.0432
82.44490.5453-0.17161.954-0.41551.9373-0.05660.38460.0801-0.2198-0.007-0.1296-0.05180.04770.07090.2893-0.01240.00890.33730.06640.2429-14.2386-13.3772-7.7435
93.26760.29360.05283.52940.28512.42420.07710.01780.33130.2373-0.17850.3321-0.1254-0.16370.08940.25570.00710.00540.34070.00660.3051-23.1342-15.2303-0.9015
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -1 through 94 )
2X-RAY DIFFRACTION2chain 'A' and (resid 95 through 203 )
3X-RAY DIFFRACTION3chain 'A' and (resid 204 through 303 )
4X-RAY DIFFRACTION4chain 'B' and (resid -1 through 62 )
5X-RAY DIFFRACTION5chain 'B' and (resid 63 through 94 )
6X-RAY DIFFRACTION6chain 'B' and (resid 95 through 183 )
7X-RAY DIFFRACTION7chain 'B' and (resid 184 through 203 )
8X-RAY DIFFRACTION8chain 'B' and (resid 204 through 274 )
9X-RAY DIFFRACTION9chain 'B' and (resid 275 through 304 )

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