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- PDB-8e6b: Crystal structure of MERS 3CL protease in complex with a dimethyl... -

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Basic information

Entry
Database: PDB / ID: 8e6b
TitleCrystal structure of MERS 3CL protease in complex with a dimethyl sulfinyl benzene inhibitor
ComponentsOrf1a protein
KeywordsHYDROLASE / Viral protein/Inhibitor / PROTEASE / protease Inhhibitors / 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-UO9 / Chem-URR / Orf1a protein
Similarity search - Component
Biological speciesMiddle East respiratory syndrome-related coronavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.55 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: 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 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: Orf1a protein
B: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,9316
Polymers68,6282
Non-polymers2,3034
Water5,603311
1
A: Orf1a protein
hetero molecules

B: Orf1a protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,9316
Polymers68,6282
Non-polymers2,3034
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_655x+1,y,z1
Buried area2530 Å2
ΔGint-18 kcal/mol
Surface area24740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.651, 105.943, 58.213
Angle α, β, γ (deg.)90.00, 108.89, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Orf1a protein


Mass: 34314.242 Da / Num. of mol.: 2 / Fragment: Full Length
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-URR / N~2~-(ethoxycarbonyl)-N-{(1S,2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-1-sulfanylpropan-2-yl}-L-leucinamide


Mass: 575.695 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H37N3O9S2
#3: Chemical ChemComp-UO9 / (2~{S})-2-[[(2~{S})-4-methyl-2-[[2-methyl-2-[oxidanyl(phenyl)-$l^{3}-sulfanyl]propoxy]carbonylamino]pentanoyl]amino]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propane-1-sulfonic acid


Mass: 575.695 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C24H37N3O9S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 311 / 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: 2.11 Å3/Da / Density % sol: 41.73 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 30% (w/v) PEG 2000 MME, 0.15 M Potassium bromide

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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: 1.55→105.94 Å / Num. obs: 78406 / % possible obs: 95.3 % / Redundancy: 3.7 % / Biso Wilson estimate: 20.9 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.044 / Rpim(I) all: 0.026 / Rrim(I) all: 0.052 / Net I/σ(I): 13.9 / Num. measured all: 293663
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
1.55-1.593.80.7972198357390.6560.470.9281.695.2
6.93-105.943.70.02934659390.9980.0170.03345.297.9

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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: 1.55→24.68 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.198 3837 4.9 %
Rwork0.174 --
obs0.175 78351 95.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.64 Å2
Refinement stepCycle: LAST / Resolution: 1.55→24.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4663 0 136 311 5110
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.55-1.570.27351350.24732730X-RAY DIFFRACTION95
1.57-1.590.25661600.24742713X-RAY DIFFRACTION95
1.59-1.610.26421550.2392774X-RAY DIFFRACTION96
1.61-1.640.26551570.2292723X-RAY DIFFRACTION95
1.64-1.660.26581260.22972815X-RAY DIFFRACTION96
1.66-1.690.27671340.21712744X-RAY DIFFRACTION96
1.69-1.710.29241460.21642805X-RAY DIFFRACTION96
1.71-1.740.24681280.2072739X-RAY DIFFRACTION96
1.74-1.770.21361360.19462806X-RAY DIFFRACTION96
1.77-1.810.22751540.1892777X-RAY DIFFRACTION96
1.81-1.850.21281140.18162803X-RAY DIFFRACTION97
1.85-1.890.22611500.16822778X-RAY DIFFRACTION96
1.89-1.930.19721670.1752773X-RAY DIFFRACTION97
1.93-1.980.19941440.17822822X-RAY DIFFRACTION97
1.98-2.030.2031090.17452822X-RAY DIFFRACTION97
2.03-2.090.22091460.16922839X-RAY DIFFRACTION97
2.09-2.160.2251600.17392820X-RAY DIFFRACTION97
2.16-2.230.19281180.1812417X-RAY DIFFRACTION97
2.26-2.320.19421110.1732033X-RAY DIFFRACTION95
2.32-2.430.22121300.18972833X-RAY DIFFRACTION97
2.43-2.560.20871490.18882805X-RAY DIFFRACTION97
2.56-2.720.21911740.18592820X-RAY DIFFRACTION98
2.72-2.930.19831660.18382834X-RAY DIFFRACTION98
2.93-3.220.22191210.19172824X-RAY DIFFRACTION97
3.22-3.690.16981470.16962847X-RAY DIFFRACTION98
3.69-4.640.16081620.1332885X-RAY DIFFRACTION99
4.64-24.680.16091380.14672933X-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)
12.1729-0.19480.75821.41970.51031.36150.08990.206-0.0555-0.1126-0.07530.06170.02940.0187-0.0040.1383-0.01020.02490.16680.00040.13838.0462-25.58562.9645
26.3138-0.25090.64236.45711.32743.53460.0760.57040.1513-0.70930.02680.2096-0.5233-0.4908-0.11930.35260.063-0.05490.41720.08290.1965-6.0244-18.5075-12.3558
31.79990.11440.15621.52220.44051.16250.01030.1541-0.0454-0.0908-0.02360.05240.03510.00110.01550.14660.0025-0.01430.1623-0.00560.13284.5707-24.05893.8957
41.1228-0.19680.99291.13070.91334.8232-0.12160.0040.3425-0.16970.005-0.0349-0.7181-0.17970.15650.28310.0146-0.00440.26790.00060.3306-2.7334-9.09759.2936
52.6762-0.7464-0.04352.09280.10031.9781-0.0299-0.240.18040.1017-0.0239-0.0009-0.09110.03930.04570.1801-0.0008-0.01020.2034-0.05330.15347.264-13.680133.3414
62.1601-0.98310.68122.5959-0.76210.72640.0275-0.1219-0.30340.06930.00030.00630.12740.0157-0.03080.19760.00860.03060.18670.02560.191-17.6847-38.298517.8972
71.7937-0.2069-0.07991.9240.27161.0918-0.0054-0.047-0.0391-0.03550.0424-0.02360.03630.0431-0.03550.14660.00430.00210.14960.00990.145-20.1015-27.110615.6044
80.767-0.89410.29033.345-1.22370.9105-0.1849-0.21490.0030.73790.07550.0201-0.22250.00340.08990.33830.0027-0.02760.2692-0.02130.2964-11.9662-20.055326.3241
93.11550.70180.44712.4894-0.06261.9513-0.10910.03790.3546-0.01920.070.0499-0.1966-0.11810.02730.19670.0058-0.00870.14380.01470.233-21.9295-0.163711.5272
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID -1 THROUGH 43 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 44 THROUGH 66 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 67 THROUGH 183 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 184 THROUGH 203 )
5X-RAY DIFFRACTION5CHAIN 'A' AND (RESID 204 THROUGH 304 )
6X-RAY DIFFRACTION6CHAIN 'B' AND (RESID -1 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 304 )

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