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- PDB-8e6e: Crystal structure of MERS 3CL protease in complex with a phenyl s... -

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Basic information

Entry
Database: PDB / ID: 8e6e
TitleCrystal structure of MERS 3CL protease in complex with a phenyl sulfane inhibitor
ComponentsOrf1a protein
KeywordsHYDROLASE / Viral protein/Inhibitor / Viral protein-Inhibitor complex
Function / homology
Function and homology information


host cell membrane / viral genome replication / methyltransferase activity / endonuclease activity / symbiont-mediated degradation of host mRNA / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / methylation / omega peptidase activity / symbiont-mediated perturbation of host ubiquitin-like protein modification ...host cell membrane / viral genome replication / methyltransferase activity / endonuclease activity / symbiont-mediated degradation of host mRNA / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / methylation / omega peptidase activity / symbiont-mediated perturbation of host ubiquitin-like protein modification / cysteine-type deubiquitinase activity / 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 / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Trypsin-like serine proteases / 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 ...Non-structural protein 2, MERS-CoV-like / NSP3, SUD-C domain, MERS-CoV-like / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / Trypsin-like serine proteases / 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 / Thrombin, subunit H / 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 / Beta Barrel / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-UUR / Chem-UV2 / Orf1a protein
Similarity search - Component
Biological speciesMiddle East respiratory syndrome-related coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.5 Å
AuthorsLiu, L. / Lovell, S. / Battaile, K.P. / Madden, T.K. / 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: Eur.J.Med.Chem. / Year: 2023
Title: Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and ...Title: Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV).
Authors: Dampalla, C.S. / Miller, M.J. / Kim, Y. / Zabiegala, A. / Nguyen, H.N. / Madden, T.K. / Thurman, H.A. / Machen, A.J. / Cooper, A. / Liu, L. / Battaile, K.P. / Lovell, S. / Chang, K.O. / Groutas, W.C.
History
DepositionAug 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 7, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3May 1, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.4Oct 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: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3783
Polymers34,3141
Non-polymers1,0632
Water3,207178
1
A: Orf1a protein
hetero molecules

A: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,7556
Polymers68,6282
Non-polymers2,1274
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area2510 Å2
ΔGint-18 kcal/mol
Surface area24640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.252, 58.087, 49.793
Angle α, β, γ (deg.)90.00, 112.39, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Orf1a protein


Mass: 34314.242 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Middle East respiratory syndrome-related coronavirus
Gene: orf1a / Plasmid: PET28 / Cell (production host): BL21(DE3) / Production host: Escherichia coli (E. coli) / References: UniProt: A0A1L2E0X0
#2: Chemical ChemComp-UUR / 2-phenylsulfanylethyl ~{N}-[(2~{S})-1-[[(1~{S},2~{S})-1-[bis(oxidanyl)-oxidanylidene-$l^{5}-sulfanyl]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate


Mass: 531.643 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H33N3O8S2
#3: Chemical ChemComp-UV2 / (1R,2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[(N-{[2-(phenylsulfanyl)ethoxy]carbonyl}-L-leucyl)amino]propane-1-sulfonic acid


Mass: 531.643 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C22H33N3O8S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 178 / 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: 37.03 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 25% (w/v) PEG 3350, 100 mM Bis-Tris

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Data collection

DiffractionMean temperature: 291 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: Jun 6, 2022
RadiationMonochromator: Double Crystal Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.5→49.22 Å / Num. obs: 42253 / % possible obs: 99.7 % / Redundancy: 3.5 % / Biso Wilson estimate: 19.46 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.031 / Rrim(I) all: 0.059 / Net I/σ(I): 11.6 / Num. measured all: 148298
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.5-1.542.90.839895930600.5950.5821.0271.398.7
6.71-49.223.50.02517384940.9990.0160.0341.898.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimless0.7.7data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WKK

5wkk


Resolution: 1.5→46.04 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.203 2082 4.93 %
Rwork0.173 --
obs0.174 42236 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.85 Å2
Refinement stepCycle: LAST / Resolution: 1.5→46.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2329 0 62 178 2569
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.530.32131240.30372633X-RAY DIFFRACTION98
1.53-1.570.26921740.25982634X-RAY DIFFRACTION100
1.57-1.620.27981350.2412668X-RAY DIFFRACTION100
1.62-1.660.23851390.21822677X-RAY DIFFRACTION100
1.66-1.720.22341120.19382689X-RAY DIFFRACTION100
1.72-1.780.21641400.19422671X-RAY DIFFRACTION100
1.78-1.850.21761360.18892682X-RAY DIFFRACTION100
1.85-1.930.2431460.18182673X-RAY DIFFRACTION100
1.93-2.040.22241420.17022655X-RAY DIFFRACTION100
2.04-2.160.2461530.16782690X-RAY DIFFRACTION100
2.16-2.330.21051340.17422679X-RAY DIFFRACTION100
2.33-2.560.20541250.18182670X-RAY DIFFRACTION100
2.56-2.940.2181340.18572717X-RAY DIFFRACTION100
2.94-3.70.20231370.16622684X-RAY DIFFRACTION99
3.7-46.040.15071510.13852732X-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)
10.6756-0.35510.33351.4934-0.69212.25770.03020.05260.0105-0.17930.00050.14270.023-0.1632-0.0340.13150.0042-0.01830.14850.00370.1485-15.376434.82725.4099
22.1997-0.5291-0.30653.82220.37892.7972-0.082-0.01490.34370.12420.01820.047-0.519-0.3130.030.28630.0434-0.06880.2060.02490.2122-16.547445.21932.8616
30.8968-0.1237-0.16212.3912-0.13691.6769-0.03270.01590.006-0.11610.0159-0.02140.0488-0.03030.0160.11860.0029-0.00980.140.00660.1088-9.331629.645910.0149
41.4845-1.60661.05821.8077-1.16661.14270.27080.0501-0.3265-0.3765-0.09480.36290.433-0.0876-0.19030.3833-0.017-0.02240.2527-0.01940.2727-11.272917.58930.3289
51.5997-0.2131-0.0272.19140.03552.41330.0188-0.0904-0.1241-0.1886-0.1447-0.28520.35620.16270.06990.18380.04670.02980.14150.04970.18326.10718.692918.5157
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 304 )

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