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- PDB-9cy0: Crystal structure of SARS-CoV-2 NSP3 macrodomain in complex with ... -

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Entry
Database: PDB / ID: 9cy0
TitleCrystal structure of SARS-CoV-2 NSP3 macrodomain in complex with AVI-4206
ComponentsPapain-like protease Non-structural protein 3
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / Macrodomain / ADP-ribose / SARS-CoV-2 / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / snRNP Assembly / Translation of Replicase and Assembly of the Replication Transcription Complex / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / host cell endoplasmic reticulum-Golgi intermediate compartment / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / symbiont-mediated degradation of host mRNA / host cell endosome / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / symbiont-mediated suppression of host toll-like receptor signaling pathway / G-quadruplex RNA binding / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated suppression of host NF-kappaB cascade / DNA helicase / symbiont-mediated perturbation of host ubiquitin-like protein modification / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / lyase activity / viral protein processing / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host gene expression / copper ion binding / symbiont-mediated activation of host autophagy / viral translational frameshifting / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding
Similarity search - Function
Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / 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. ...Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / 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 / : / Lipocalin signature. / DNA2/NAM7 helicase-like, C-terminal / AAA domain / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus / Sarbecovirus Nsp3c-N domain profile. / Non-structural protein NSP3, N-terminal, betacoronavirus / Polyprotein cleavage domain PL2pro superfamily, betacoronavirus / Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus / Betacoronavirus SUD-C domain / Betacoronavirus replicase NSP3, N-terminal / NSP1 globular domain superfamily, betacoronavirus / Non-structural protein 2, SARS-CoV-like / Betacoronavirus single-stranded poly(A) binding domain / 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 / 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 / Carbamoyl-phosphate synthase subdomain signature 2. / Coronavirus replicase NSP2, N-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 Nsp3 ectodomain (3Ecto) profile.
Similarity search - Domain/homology
: / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 0.8 Å
AuthorsCorrey, G.J. / Fraser, J.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19AI171110 United States
CitationJournal: To Be Published
Title: Ligand screen against SARS-CoV-2 NSP3 macrodomain
Authors: Correy, G.J. / Fraser, J.S.
History
DepositionAug 1, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Papain-like protease Non-structural protein 3
B: Papain-like protease Non-structural protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3144
Polymers36,5522
Non-polymers7632
Water7,224401
1
A: Papain-like protease Non-structural protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6572
Polymers18,2761
Non-polymers3811
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Papain-like protease Non-structural protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6572
Polymers18,2761
Non-polymers3811
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)30.294, 39.784, 64.392
Angle α, β, γ (deg.)89.93, 77.81, 90.08
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Papain-like protease Non-structural protein 3 / nsp3 / PL2-PRO / Papain-like protease / Papain-like proteinase / PL-PRO


Mass: 18275.771 Da / Num. of mol.: 2 / Fragment: macrodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0DTD1, EC: 3.4.19.121, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Chemical ChemComp-A1A55 / N-{4-[(2,2-dimethyl-5-oxopyrrolidin-1-yl)amino]-9H-pyrimido[4,5-b]indol-8-yl}-N'-ethylurea / AVI-4206


Mass: 381.432 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H23N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 401 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.08 Å3/Da / Density % sol: 40.73 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / Details: 200 mM lithium acetate, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 0.77487 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 29, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.77487 Å / Relative weight: 1
ReflectionResolution: 0.8→39.78 Å / Num. obs: 235533 / % possible obs: 76 % / Redundancy: 1.8 % / CC1/2: 0.997 / Rmerge(I) obs: 0.031 / Rrim(I) all: 0.043 / Net I/σ(I): 13.1
Reflection shellResolution: 0.8→0.85 Å / Num. unique obs: 17761 / CC1/2: 0.76 / Rrim(I) all: 0.47

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
XDSJun. 30, 2023data scaling
XDSJun. 30, 2023data reduction
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 0.8→39.78 Å / SU ML: 0.07 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 20.77 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1853 11752 4.99 %
Rwork0.1587 --
obs0.16 235323 75.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 0.8→39.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2546 0 56 401 3003
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095499
X-RAY DIFFRACTIONf_angle_d0.9977485
X-RAY DIFFRACTIONf_dihedral_angle_d13.4391965
X-RAY DIFFRACTIONf_chiral_restr0.073863
X-RAY DIFFRACTIONf_plane_restr0.008959
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
0.8-0.810.3244720.3261495X-RAY DIFFRACTION15
0.81-0.820.3061890.28591923X-RAY DIFFRACTION19
0.82-0.830.26341420.26212436X-RAY DIFFRACTION25
0.83-0.840.27451430.25592903X-RAY DIFFRACTION29
0.84-0.850.27711870.2523595X-RAY DIFFRACTION37
0.85-0.860.27682020.28124218X-RAY DIFFRACTION42
0.86-0.870.25252310.2295130X-RAY DIFFRACTION52
0.87-0.890.25623150.21416358X-RAY DIFFRACTION64
0.89-0.90.2264240.20568162X-RAY DIFFRACTION83
0.9-0.920.22784940.18828609X-RAY DIFFRACTION87
0.92-0.930.20854920.18428508X-RAY DIFFRACTION88
0.93-0.950.18624990.18028631X-RAY DIFFRACTION88
0.95-0.970.20194410.17078626X-RAY DIFFRACTION88
0.97-0.990.17163910.16758719X-RAY DIFFRACTION88
0.99-1.010.19654740.16868722X-RAY DIFFRACTION89
1.01-1.030.17464570.16238660X-RAY DIFFRACTION89
1.03-1.060.17434570.14858733X-RAY DIFFRACTION89
1.06-1.090.16284730.14358775X-RAY DIFFRACTION89
1.09-1.120.15534750.13718627X-RAY DIFFRACTION88
1.12-1.150.1594760.13698761X-RAY DIFFRACTION90
1.15-1.20.15634900.13748891X-RAY DIFFRACTION91
1.2-1.240.16054810.13888922X-RAY DIFFRACTION91
1.24-1.30.16684380.13749075X-RAY DIFFRACTION92
1.3-1.370.17324420.1419223X-RAY DIFFRACTION93
1.37-1.450.15595170.14149175X-RAY DIFFRACTION94
1.45-1.570.16784950.1429242X-RAY DIFFRACTION94
1.57-1.720.16995390.14929233X-RAY DIFFRACTION94
1.72-1.970.18414880.15789253X-RAY DIFFRACTION95
1.97-2.490.19554480.1569432X-RAY DIFFRACTION95
2.49-39.780.21034800.17629534X-RAY DIFFRACTION97

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