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- PDB-6w81: Structure of PEDV main protease bound to potent broad-spectrum no... -

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Basic information

Entry
Database: PDB / ID: 6w81
TitleStructure of PEDV main protease bound to potent broad-spectrum non-covalent inhibitor X77
ComponentsPeptidase C30
KeywordsVIRAL PROTEIN/INHIBITOR / COVID-19 / porcine epidemic diarrhea virus / PEDV / main protease / 3C-like protease / 3CL protease / 3Clpro / Mpro / broad-spectrum / inhibitor / proteinase / non-covalent / reversible / Structural Genomics / Center for Structural Genomics of Infectious Diseases / CSGID / ANTIVIRAL PROTEIN / VIRAL PROTEIN / VIRAL PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


: / host cell membrane / viral genome replication / host cell endoplasmic reticulum-Golgi intermediate compartment / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / endonuclease activity / 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 ...: / host cell membrane / viral genome replication / host cell endoplasmic reticulum-Golgi intermediate compartment / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / endonuclease activity / 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 / methyltransferase cap1 activity / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / viral protein processing / lyase activity / host cell perinuclear region of cytoplasm / viral translational frameshifting / symbiont-mediated activation of host autophagy / cysteine-type endopeptidase activity / RNA-directed RNA polymerase activity / DNA-templated transcription / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / : / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain / Pectin lyase fold/virulence factor / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 ...Nonstructural protein 14, alphacoronavirus / RNA-dependent RNA polymerase, alphacoronavirus / : / Non-structural protein 5, alphacoronavirus / Non-structural protein 6, alphacoronavirus / Nonstructural protein 2, HCoV-229E-like / AAA domain / Pectin lyase fold/virulence factor / main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / NSP15, NendoU domain, coronavirus / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / : / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Coronavirus Nsp12 Interface domain profile. / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Nidovirus 2-O-methyltransferase / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP15, N-terminal domain superfamily, coronavirus / Non-structural protein NSP15, middle domain superfamily / Coronavirus replicase NSP15, N-terminal oligomerization / Nonstructural protein 15, middle domain, coronavirus / Nonstructural protein 13, 1B domain, coronavirus / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) domain profile. / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Endoribonuclease EndoU-like / NendoU domain, nidovirus / Coronavirus replicase NSP15, uridylate-specific endoribonuclease / : / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Trypsin-like serine proteases / 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
Similarity search - Domain/homology
MALONIC ACID / Chem-X77 / ORF1ab polyprotein
Similarity search - Component
Biological speciesPorcine epidemic diarrhea virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsMesecar, A.D. / Center for Structural Genomics of Infectious Diseases (CSGID)
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HHSN272201700060C United States
CitationJournal: To Be Published
Title: A taxonomically-driven approach to development of potent, broad-spectrum inhibitors of coronavirus main protease including SARS-CoV-2 (COVID-19)
Authors: Mesecar, A.D.
History
DepositionMar 20, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 24, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Peptidase C30
B: Peptidase C30
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,6635
Polymers65,6402
Non-polymers1,0233
Water9,620534
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, PEDV 3CLpro aka main protease runs as a dimer on a SEC column
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3290 Å2
ΔGint-14 kcal/mol
Surface area24520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.679, 85.257, 58.186
Angle α, β, γ (deg.)90.000, 100.460, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Peptidase C30 / main protease


Mass: 32820.121 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Porcine epidemic diarrhea virus / Gene: ORF1ab / Production host: Escherichia coli (E. coli) / References: UniProt: S0AP56
#2: Chemical ChemComp-X77 / N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide


Mass: 459.583 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MLA / MALONIC ACID / DICARBOXYLIC ACID C3 / PROPANEDIOLIC ACID / METHANEDICARBOXYLIC ACID


Mass: 104.061 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 534 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 41.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4
Details: PEDV-3CLpro:77 inhibitor complex was co-crystallized by setting up 2 uL drops that were composed of 1 uL of purified PEDV-3CLpro (2.4 mg/mL) that had been incubated for three hours with a 3 ...Details: PEDV-3CLpro:77 inhibitor complex was co-crystallized by setting up 2 uL drops that were composed of 1 uL of purified PEDV-3CLpro (2.4 mg/mL) that had been incubated for three hours with a 3 molar excess of compound 77, and 1 uL of reservoir solution: 0.20 M malonic acid (MIB) pH 4.0 and 25% PEG-3350
Temp details: Room temperature

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: Dry nitrogen stream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.988 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.988 Å / Relative weight: 1
ReflectionResolution: 1.55→50 Å / Num. obs: 76919 / % possible obs: 97.8 % / Redundancy: 4.8 % / Biso Wilson estimate: 20.34 Å2 / Rpim(I) all: 0.04 / Rrim(I) all: 0.086 / Χ2: 1.9 / Net I/σ(I): 28.9
Reflection shellResolution: 1.55→1.58 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.739 / Mean I/σ(I) obs: 1.35 / Num. unique obs: 3111 / CC1/2: 0.637 / CC star: 0.882 / Rpim(I) all: 0.469 / Χ2: 0.849 / % possible all: 79.2

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5HYO

5hyo


Resolution: 1.55→27.87 Å / SU ML: 0.2102 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.366
RfactorNum. reflection% reflection
Rfree0.2136 1998 2.6 %
Rwork0.1758 --
obs0.1768 76888 97.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 34.69 Å2
Refinement stepCycle: LAST / Resolution: 1.55→27.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4590 0 75 534 5199
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00584820
X-RAY DIFFRACTIONf_angle_d0.84096566
X-RAY DIFFRACTIONf_chiral_restr0.0519739
X-RAY DIFFRACTIONf_plane_restr0.0045845
X-RAY DIFFRACTIONf_dihedral_angle_d14.76672775
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.55-1.590.33581090.29334099X-RAY DIFFRACTION75.05
1.59-1.630.341340.28494992X-RAY DIFFRACTION91.1
1.63-1.680.331370.27545399X-RAY DIFFRACTION98.37
1.68-1.730.28881480.24875474X-RAY DIFFRACTION99.91
1.73-1.790.22941460.2225446X-RAY DIFFRACTION100
1.79-1.870.27621490.20615473X-RAY DIFFRACTION100
1.87-1.950.27381420.20265495X-RAY DIFFRACTION100
1.95-2.050.25651430.20525449X-RAY DIFFRACTION100
2.05-2.180.26171470.19585511X-RAY DIFFRACTION99.98
2.18-2.350.25851450.18915486X-RAY DIFFRACTION99.98
2.35-2.590.21981450.18265480X-RAY DIFFRACTION100
2.59-2.960.19671480.18215509X-RAY DIFFRACTION99.96
2.96-3.730.18891500.1545514X-RAY DIFFRACTION99.95
3.73-27.870.15391550.12855563X-RAY DIFFRACTION99.43
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)
12.137376127470.991317003849-1.046806492761.12756125739-0.822765900853.087752358890.0929751449733-0.05939636600960.02325666049240.00496590061173-0.007842036263620.0167738969253-0.0756856827820.152255696657-0.07748760824470.1472685120320.01377413459630.01263006534850.115101168138-0.03068507054750.126852154337-28.533526565673.24507151637.6247163478
21.89263466620.864439722592-0.270185945251.94513488358-0.7429576669633.475086318530.01705402117790.009308055352750.161793285841-0.07323792303930.0268610285123-0.110747445526-0.2903331387540.264609578505-0.007632041836630.1619841975560.02324016621210.03365124964340.172818704987-0.0358058575140.170160378058-23.589483671774.6163059502-1.00199707211
32.438231577880.927847263407-0.2293750881291.16686419426-0.667748525871.866104765480.06513007005850.09461994008310.0343810982751-0.05546540036310.0171787783410.1125928267330.0576515248535-0.254527341212-0.09306443815850.145335752927-0.00315214013319-0.008261784164580.1535702100820.01039341326430.130737177417-40.416312911268.05910377764.33321123069
40.661159474670.0737933862874-0.547260163632.01831802392-1.779072737782.214765978910.533340935786-0.322681317945-0.807547948827-0.260893283443-0.1046781765780.1177279505580.855220240008-0.72521816892-0.1790965224710.420594431726-0.253494477797-0.1742292699850.51820629870.1262717989660.457231157543-59.037693654749.71510872027.29849686191
56.15188254399-3.328290023950.9829779931015.85287175742-0.7571248718654.656818314660.160561810848-0.453116137457-0.003771953563260.0738488033969-0.0511871817522-0.05414739865980.189014100511-0.357350672238-0.1008667963740.187371268249-0.141060272104-0.04189252154420.2510994132980.01732321904590.176705324986-52.756064203958.322733013314.7164483163
61.36157336327-0.7542646635120.7239697631521.21878874946-1.302225262434.180955985790.00577143825294-0.157741353896-0.1033675326710.0287032887942-0.01101013718050.03958104642030.359080683674-0.08904920414990.02915732487820.195631583036-0.03884987668060.01646414772710.148879385723-0.0003442166485810.13152056952-34.317843365560.508091061234.5023340923
70.467196527239-0.319396429799-0.1861852540781.47348570114-0.5253974947323.0487944072-0.0110169165978-0.0743756272061-0.03622521340180.101721192444-0.0938156381459-0.1732676401390.08262233778720.2391130134150.1081164255070.162878970751-0.0345691406888-0.01385786374550.2183898688950.03005610112990.188897898579-30.153247739262.645196828139.3415148562
84.24809366669-4.71436053644-4.801211437476.539144306583.958646426026.71212425983-0.0254566426705-0.04090807122090.0675676480921-0.02044846548290.04665021127460.2005846033450.0682283260745-0.5329601036510.02442272336690.17522453584-0.0298787314401-0.02679220377150.3137341800340.02842122193110.155739852101-46.170888012566.460444313228.2715823712
91.72537446681-0.9205493896141.704570283030.978526604089-0.525772406021.764975897730.0572386571661-0.314633676836-0.103161793330.06244958001290.004286587915410.1400979186180.0969030556301-0.448262405281-0.04781637036350.17494502794-0.03493547980120.02003388942440.291144952670.005847664032370.150795562898-46.266984695468.154039387332.2690055441
102.77725437624-0.25818895785-2.690387654921.662478606540.3473440783177.459531739060.066050022844-0.7093709325650.7262173847780.110639581509-0.4720030016830.609113743483-0.543322791705-0.2081831327280.1246068950210.22155383640.01226872992060.02967676234420.622472475641-0.2795746124450.430661121692-64.394850628583.032098310323.466709417
114.559218072421.1048468759-0.3653516972724.953300032790.6747343715632.252161125110.0813112147439-0.4234117078160.307996734299-0.211225791616-0.2678137837420.108526886432-0.335712680844-0.2611221264910.1452382132660.1904041785860.0618700377928-0.02171154569330.272242420603-0.05817947672710.172742393994-55.195919213881.792408186318.6276236005
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 109 )
3X-RAY DIFFRACTION3chain 'A' and (resid 110 through 212 )
4X-RAY DIFFRACTION4chain 'A' and (resid 213 through 268 )
5X-RAY DIFFRACTION5chain 'A' and (resid 269 through 300 )
6X-RAY DIFFRACTION6chain 'B' and (resid 1 through 52 )
7X-RAY DIFFRACTION7chain 'B' and (resid 53 through 119 )
8X-RAY DIFFRACTION8chain 'B' and (resid 120 through 138 )
9X-RAY DIFFRACTION9chain 'B' and (resid 139 through 212 )
10X-RAY DIFFRACTION10chain 'B' and (resid 213 through 243 )
11X-RAY DIFFRACTION11chain 'B' and (resid 244 through 300 )

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