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

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Basic information

Entry
Database: PDB / ID: 9ath
TitleCrystal structure of MERS 3CL protease in complex with a methylbicyclo[2.2.1]heptene 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: 1.65 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 16, 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)71,0236
Polymers68,6282
Non-polymers2,3954
Water5,405300
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1900 Å2
ΔGint-7 kcal/mol
Surface area25170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.807, 106.232, 58.215
Angle α, β, γ (deg.)90.00, 109.23, 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-A1AGR / (1S,2S)-2-{[N-({[(2S)-1-{[(1R,2S,4R)-bicyclo[2.2.1]hept-5-en-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: 598.709 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H42N4O9S
#3: Chemical ChemComp-A1AGQ / (1R,2S)-2-{[N-({[(2S)-1-{[(1R,2S,4R)-bicyclo[2.2.1]hept-5-en-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: 598.709 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C27H42N4O9S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 300 / 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: 41.95 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 800 mM potassium sodium tartrate tetrahydrate, 100 mM Tris, pH 8.5, 0.5% w/v PEG5000 MME

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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: 1.65→106.23 Å / Num. obs: 68325 / % possible obs: 99.6 % / Redundancy: 4.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.108 / Rpim(I) all: 0.06 / Rrim(I) all: 0.124 / Χ2: 0.94 / Net I/σ(I): 8.8 / Num. measured all: 289398
Reflection shellResolution: 1.65→1.69 Å / % possible obs: 99.7 % / Redundancy: 4.4 % / Rmerge(I) obs: 1.093 / Num. measured all: 21944 / Num. unique obs: 5035 / CC1/2: 0.476 / Rpim(I) all: 0.585 / Rrim(I) all: 1.243 / Χ2: 0.92 / Net I/σ(I) obs: 1.5

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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: 1.65→47.03 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.17 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2085 3334 4.88 %
Rwork0.1821 --
obs0.1834 68258 99.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.65→47.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4627 0 148 300 5075
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065088
X-RAY DIFFRACTIONf_angle_d0.8846978
X-RAY DIFFRACTIONf_dihedral_angle_d14.7321870
X-RAY DIFFRACTIONf_chiral_restr0.054806
X-RAY DIFFRACTIONf_plane_restr0.006887
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.670.25521310.26712687X-RAY DIFFRACTION100
1.67-1.70.2751440.27552730X-RAY DIFFRACTION100
1.7-1.730.32211510.26862661X-RAY DIFFRACTION100
1.73-1.750.30081170.25962735X-RAY DIFFRACTION100
1.75-1.780.26791560.25262678X-RAY DIFFRACTION100
1.78-1.820.24041460.23692704X-RAY DIFFRACTION100
1.82-1.850.26771350.2112710X-RAY DIFFRACTION100
1.85-1.890.25781420.2042688X-RAY DIFFRACTION100
1.89-1.930.25211170.2082741X-RAY DIFFRACTION100
1.93-1.970.24361320.20882655X-RAY DIFFRACTION100
1.97-2.020.24781350.19772742X-RAY DIFFRACTION100
2.02-2.080.21931330.19712736X-RAY DIFFRACTION100
2.08-2.140.21711390.17572670X-RAY DIFFRACTION100
2.14-2.210.21661500.18452710X-RAY DIFFRACTION100
2.21-2.290.21681240.17952718X-RAY DIFFRACTION100
2.29-2.380.24651340.1852727X-RAY DIFFRACTION100
2.38-2.490.22791410.18772711X-RAY DIFFRACTION100
2.49-2.620.20011520.18922718X-RAY DIFFRACTION100
2.62-2.780.23111470.18962692X-RAY DIFFRACTION100
2.78-30.20971480.18592689X-RAY DIFFRACTION99
3-3.30.22081570.17652651X-RAY DIFFRACTION98
3.3-3.780.16581290.15562679X-RAY DIFFRACTION98
3.78-4.760.14371430.14012713X-RAY DIFFRACTION99
4.76-47.030.15951310.15462779X-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)
11.57320.81930.41691.71890.32520.50240.01360.099-0.2137-0.0140.01710.0110.11470.0019-0.02470.1729-0.00240.02080.1335-0.01930.14938.3999-38.537610.0039
21.13220.0568-0.09871.4180.07460.78770.01270.04760.0289-0.02660.01430.02880.005-0.0459-0.02110.1275-0.0008-0.00010.1173-0.00290.11778.8596-25.89489.7819
32.005-0.50030.21731.3264-0.05861.171-0.027-0.03660.30490.0170.008-0.0546-0.12670.074-0.00030.1711-0.00520.01080.1188-0.00790.207212.278-0.170415.971
41.57150.00960.68040.4969-0.52780.81770.0897-0.1183-0.0593-0.0097-0.0678-0.03680.05520.0144-0.0130.130.00590.01370.1222-0.00950.1112-17.3023-26.072125.4691
52.9571-0.43060.63922.842-1.3742.44590.1208-0.39860.35160.20670.01520.1438-0.54850.35650.05770.2365-0.0581-0.02220.3112-0.06380.2115-2.7187-16.267539.0504
62.07210.48070.21450.95480.00730.33780.1385-0.3049-0.21880.0692-0.0860.05460.1338-0.0639-0.01430.2168-0.0116-0.03110.23540.03390.1786-11.1354-30.701936.3438
71.4062-0.08520.08181.0122-0.54790.94820.0273-0.01830.00450.0163-0.0015-0.04540.0662-0.0193-0.0150.1277-0.0007-0.00160.1186-0.00040.0982-15.2775-22.302820.4277
80.56430.14070.36670.2328-0.31832.0429-0.0063-0.04670.17530.0621-0.02520.0541-0.51070.09040.05720.2615-0.03020.00160.21630.00430.2422-6.9739-9.471918.6365
91.89560.30690.11790.905-0.18691.1086-0.00770.27740.1233-0.09440.0204-0.07-0.0375-0.015-0.00390.14270.00010.01410.16240.04610.1194-14.3376-13.1464-7.6406
102.34910.18820.3811.5934-0.16861.58390.02440.03110.18370.2882-0.0620.1245-0.0839-0.1039-0.00720.13730.02140.01450.17470.00260.1626-23.1552-15.0641-0.8953
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 0 through 43 )
5X-RAY DIFFRACTION5chain 'B' and (resid 44 through 62 )
6X-RAY DIFFRACTION6chain 'B' and (resid 63 through 94 )
7X-RAY DIFFRACTION7chain 'B' and (resid 95 through 183 )
8X-RAY DIFFRACTION8chain 'B' and (resid 184 through 203 )
9X-RAY DIFFRACTION9chain 'B' and (resid 204 through 274 )
10X-RAY DIFFRACTION10chain 'B' and (resid 275 through 304 )

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