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

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Entry
Database: PDB / ID: 9cxz
TitleCrystal structure of SARS-CoV-2 NSP3 macrodomain in complex with AVI-1501
ComponentsNon-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 / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / snRNP Assembly ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / snRNP Assembly / Transcription of SARS-CoV-2 sgRNAs / 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 endosome / host cell endoplasmic reticulum-Golgi intermediate compartment / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host toll-like receptor signaling pathway / G-quadruplex RNA binding / symbiont-mediated suppression of host ISG15-protein conjugation / mRNA guanylyltransferase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / DNA helicase / omega peptidase activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / symbiont-mediated suppression of host NF-kappaB cascade / SARS-CoV-2 modulates host translation machinery / symbiont-mediated perturbation of host ubiquitin-like protein modification / host cell Golgi apparatus / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / methyltransferase cap1 activity / lyase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / cysteine-type deubiquitinase activity / single-stranded RNA binding / 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 / viral translational frameshifting / symbiont-mediated activation of host autophagy / cysteine-type endopeptidase activity / RNA-directed RNA polymerase / viral RNA genome replication / RNA-directed RNA polymerase activity / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / DNA-templated transcription / proteolysis / RNA binding / zinc ion binding / ATP binding
Similarity search - Function
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 / : ...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 (AV-Nsp11N/CoV-Nsp15M) domain profile. / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / 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 profile. / (+) RNA virus helicase core domain / 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 / Coronavirus Nsp6 transmembrane protein profile. / Coronavirus Nsp4 ectodomain (4Ecto) profile. / 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 Nsp3 ectodomain (3Ecto) profile. / Coronavirus RNA-dependent RNA polymerase (RdRp) Nsp7 cofactor domain 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: 1.02 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 1.0Apr 8, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)36,7174
Polymers36,3582
Non-polymers3602
Water7,314406
1
A: Non-structural protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5393
Polymers18,1791
Non-polymers3602
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Non-structural protein 3


Theoretical massNumber of molelcules
Total (without water)18,1791
Polymers18,1791
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.897, 88.897, 39.408
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number78
Space group name H-MP43
Symmetry operation#1: x,y,z
#2: -y,x,z+3/4
#3: y,-x,z+1/4
#4: -x,-y,z+1/2

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Components

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


Mass: 18178.766 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-A1A54 / N-{4-[(2-oxopyrrolidin-1-yl)amino]-9H-pyrimido[4,5-b]indol-8-yl}acetamide / AVI-1501


Mass: 324.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 406 / 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: 2.14 Å3/Da / Density % sol: 42.56 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 9.5 / Details: 100 mM CHES, 28% PEG 3000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 0.88557 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 29, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.88557 Å / Relative weight: 1
ReflectionResolution: 1.02→44.45 Å / Num. obs: 156117 / % possible obs: 99.7 % / Redundancy: 6.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.032 / Rrim(I) all: 0.046 / Net I/σ(I): 7.02
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.02-1.080.762148170.6641.0781
1.08-1.160.377144360.8810.5331
1.16-1.250.193142950.9590.2731
1.25-1.370.124126630.9830.1751
1.37-1.530.077120300.9890.1091
1.53-1.770.045102150.9940.0641
1.77-2.160.02988740.9970.0411
2.16-3.050.02666490.9970.0371
3.05-44.450.02437770.9960.0341

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
XDSJun. 30, 2023data reduction
XDSJun. 30, 2023data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.02→44.45 Å / SU ML: 0.1 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1596 7524 4.82 %
Rwork0.1426 --
obs0.1435 156005 99.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.02→44.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2556 0 25 406 2987
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072695
X-RAY DIFFRACTIONf_angle_d0.8953675
X-RAY DIFFRACTIONf_dihedral_angle_d11.714966
X-RAY DIFFRACTIONf_chiral_restr0.068426
X-RAY DIFFRACTIONf_plane_restr0.008477
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.02-1.030.37641910.41464669X-RAY DIFFRACTION93
1.03-1.040.37222830.34974900X-RAY DIFFRACTION100
1.04-1.060.28832660.29664925X-RAY DIFFRACTION100
1.06-1.070.28192870.27474917X-RAY DIFFRACTION100
1.07-1.080.27262510.25614891X-RAY DIFFRACTION100
1.08-1.10.25952190.24064965X-RAY DIFFRACTION100
1.1-1.110.24222650.22274869X-RAY DIFFRACTION100
1.11-1.130.22362250.20985012X-RAY DIFFRACTION100
1.13-1.150.20492360.19274888X-RAY DIFFRACTION100
1.15-1.170.20112630.1754983X-RAY DIFFRACTION100
1.17-1.190.19162550.16334934X-RAY DIFFRACTION100
1.19-1.210.18242640.15314862X-RAY DIFFRACTION100
1.21-1.230.17312210.14565046X-RAY DIFFRACTION100
1.23-1.260.16152370.14034899X-RAY DIFFRACTION100
1.26-1.290.16322580.13764918X-RAY DIFFRACTION100
1.29-1.320.15252680.13584971X-RAY DIFFRACTION100
1.32-1.350.16032410.13824949X-RAY DIFFRACTION100
1.35-1.380.15592620.13554896X-RAY DIFFRACTION100
1.38-1.430.18222350.13254979X-RAY DIFFRACTION100
1.43-1.470.14692460.12984971X-RAY DIFFRACTION100
1.47-1.520.12652410.12264976X-RAY DIFFRACTION100
1.52-1.580.14142670.11644947X-RAY DIFFRACTION100
1.58-1.660.13472680.11784940X-RAY DIFFRACTION100
1.66-1.740.13382000.12545060X-RAY DIFFRACTION100
1.74-1.850.15182860.12974936X-RAY DIFFRACTION100
1.85-20.13942510.13194995X-RAY DIFFRACTION100
2-2.20.14282890.1314950X-RAY DIFFRACTION100
2.2-2.520.15132450.13215025X-RAY DIFFRACTION100
2.52-3.170.16562530.13985025X-RAY DIFFRACTION100
3.17-44.450.15072510.13795183X-RAY DIFFRACTION100

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