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- PDB-9atf: Crystal structure of MERS 3CL protease in complex with a 1-methyl... -

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Basic information

Entry
Database: PDB / ID: 9atf
TitleCrystal structure of MERS 3CL protease in complex with a 1-methyl-4,4-difluorocyclohexyl 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 / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / omega peptidase activity / 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 / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / symbiont-mediated perturbation of host ubiquitin-like protein modification / endonuclease activity / ubiquitinyl hydrolase 1 / methylation / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell perinuclear region of cytoplasm / viral protein processing / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / viral translational frameshifting / cysteine-type endopeptidase activity / virus-mediated perturbation of host defense response / 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 / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp2 middle domain profile. / 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 / : / : / Coronavirus replicase NSP7 / Peptidase family C16 domain profile. / 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. / 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 main protease (M-pro) domain profile. / Coronavirus replicase NSP9 / Non-structural protein 3, X-domain-like / Macro domain / Appr-1"-p processing enzyme / Macro domain / Macro domain profile. / 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: 1.5 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)35,5643
Polymers34,3141
Non-polymers1,2492
Water3,639202
1
A: 3C-like proteinase nsp5
hetero molecules

A: 3C-like proteinase nsp5
hetero molecules


  • defined by author&software
  • Evidence: gel filtration
  • 71.1 kDa, 2 polymers
Theoretical massNumber of molelcules
Total (without water)71,1276
Polymers68,6282
Non-polymers2,4994
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area3050 Å2
ΔGint-17 kcal/mol
Surface area25250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.125, 58.034, 49.970
Angle α, β, γ (deg.)90.00, 112.51, 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-A1AGP / (1S,2S)-2-({N-[({(2S)-1-[(4,4-difluorocyclohexyl)methyl]-5-oxopyrrolidin-2-yl}methoxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 624.695 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H42F2N4O9S
#3: Chemical ChemComp-A1AGO / (1R,2S)-2-({N-[({(2S)-1-[(4,4-difluorocyclohexyl)methyl]-5-oxopyrrolidin-2-yl}methoxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 624.695 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C26H42F2N4O9S
#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: 1.97 Å3/Da / Density % sol: 37.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 25% w/v PEG3350, 100 mM Bis-Tris, pH 5.5, 200 mM sodium chloride

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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: 1.5→49.3 Å / Num. obs: 42470 / % possible obs: 99.3 % / Redundancy: 5.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.075 / Rpim(I) all: 0.033 / Rrim(I) all: 0.083 / Χ2: 1.01 / Net I/σ(I): 11.8 / Num. measured all: 252077
Reflection shellResolution: 1.5→1.53 Å / % possible obs: 98.2 % / Redundancy: 6.1 % / Rmerge(I) obs: 1.017 / Num. measured all: 12695 / Num. unique obs: 2070 / CC1/2: 0.827 / Rpim(I) all: 0.443 / Rrim(I) all: 1.111 / Χ2: 1.07 / 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: 1.5→23.35 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.01 / Phase error: 18.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1786 2101 4.95 %
Rwork0.1552 --
obs0.1564 42428 99.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.5→23.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2291 0 76 202 2569
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092502
X-RAY DIFFRACTIONf_angle_d0.9663439
X-RAY DIFFRACTIONf_dihedral_angle_d13.04916
X-RAY DIFFRACTIONf_chiral_restr0.056403
X-RAY DIFFRACTIONf_plane_restr0.009434
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.530.26621130.24522669X-RAY DIFFRACTION98
1.53-1.570.27591320.22082667X-RAY DIFFRACTION98
1.57-1.620.2131490.20282637X-RAY DIFFRACTION99
1.62-1.660.24581510.19642650X-RAY DIFFRACTION99
1.66-1.720.23881350.1852649X-RAY DIFFRACTION99
1.72-1.780.19811380.17882680X-RAY DIFFRACTION99
1.78-1.850.20341410.1732669X-RAY DIFFRACTION99
1.85-1.930.1891540.15232666X-RAY DIFFRACTION99
1.93-2.040.17891390.14252690X-RAY DIFFRACTION99
2.04-2.160.18151220.14142735X-RAY DIFFRACTION100
2.16-2.330.16461620.14462703X-RAY DIFFRACTION100
2.33-2.560.18171360.15222684X-RAY DIFFRACTION100
2.56-2.930.16271450.1552725X-RAY DIFFRACTION100
2.93-3.690.17031380.1472718X-RAY DIFFRACTION99
3.7-23.350.15731460.14362785X-RAY DIFFRACTION100
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)
11.3653-1.03450.76821.4259-0.43840.56360.12520.0432-0.2978-0.18160.01030.37080.2804-0.1402-0.15040.2917-0.0046-0.02310.2415-0.0220.2607-11.0118-12.41770.5424
21.4222-0.0122-0.20251.5382-0.07311.8207-0.0225-0.1382-0.2012-0.1365-0.1012-0.16540.30380.16360.09950.19520.05050.03050.15320.05080.19486.2069-21.25518.5387
31.0285-0.3210.07381.1551-0.46261.81870.0340.1166-0.0147-0.15110.00430.12260.0031-0.1982-0.05330.1494-0.0007-0.01850.1590.00310.15-15.10774.94586.0235
41.87810.04-0.48032.21090.13882.2475-0.08480.00510.3550.15170.08760.1533-0.5556-0.18090.0060.310.0575-0.03840.20620.03850.2142-16.536915.33332.7945
50.7028-0.2371-0.14061.65810.01591.4377-0.04770.0245-0.0059-0.06340.0184-0.0375-0.0021-0.01520.02940.1170.0007-0.00540.13160.00790.1198-9.4345-0.29410.0192
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 184 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 )
5X-RAY DIFFRACTION5chain 'A' and (resid 95 through 183 )

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