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- PDB-7h0b: Crystal structure of SARS-CoV-2 NSP3 Macrodomain in complex with ... -

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Basic information

Entry
Database: PDB / ID: 7h0b
TitleCrystal structure of SARS-CoV-2 NSP3 Macrodomain in complex with ASAP-0010716-001
ComponentsPapain-like protease nsp3
KeywordsVIRAL PROTEIN / Hydrolase / ASAP / AViDD / Diamond I04-1 / crystallographic fragment screening / PanDDA / XChemExplorer / SARS-CoV-2
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters / mRNA guanylyltransferase activity / 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 / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs ...protein guanylyltransferase activity / RNA endonuclease activity, producing 3'-phosphomonoesters / mRNA guanylyltransferase activity / 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 / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / TRAF3-dependent IRF activation pathway / Replication of the SARS-CoV-2 genome / snRNP Assembly / double membrane vesicle viral factory outer membrane / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / : / SARS coronavirus main proteinase / host cell endosome / 3'-5'-RNA exonuclease activity / host cell endoplasmic reticulum-Golgi intermediate compartment / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / SARS-CoV-2 modulates host translation machinery / omega peptidase activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / mRNA (guanine-N7)-methyltransferase / host cell Golgi apparatus / methyltransferase cap1 / symbiont-mediated perturbation of host ubiquitin-like protein modification / mRNA (nucleoside-2'-O-)-methyltransferase activity / DNA helicase / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / viral protein processing / lyase activity / RNA helicase / induction by virus of host autophagy / copper ion binding / RNA-directed RNA polymerase / symbiont-mediated suppression of host gene expression / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / DNA-templated transcription / lipid binding / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane
Similarity search - Function
RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / : / Coronavirus Nsp12 Interface domain profile. ...RNA-dependent RNA polymerase, SARS-CoV-like / Nonstructural protein 14, betacoronavirus / NSP15, NendoU domain, coronavirus / : / : / Coronavirus Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / : / Coronavirus Nsp12 Interface domain profile. / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / NSP12 RNA-dependent RNA polymerase, coronavirus / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Nidovirus 2-O-methyltransferase / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) domain profile. / Nidovirus 3'-5' exoribonuclease domain / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / Nonstructural protein 13, 1B domain, coronavirus / Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain / 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 / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Arterivirus Nsp11 N-terminal/coronavirus NSP15 middle (AV-Nsp11N/CoV-Nsp15M) 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 / Nidoviral uridylate-specific endoribonuclease (NendoU) domain profile. / Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain / Nonstructural protein 13, zinc-binding domain, coronavirus-like / Coronaviridae zinc-binding (CV ZBD) domain profile. / 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 / Lipocalin signature. / (+) 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 / Carbamoyl-phosphate synthase subdomain signature 2. / Coronavirus 3Ecto domain profile. / : / Betacoronavirus Nsp3e group 2-specific marker (G2M) domain profile. / NSP1, C-terminal domain, betacoronavirus / 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 / Betacoronavirus (BetaCoV) Nsp1 C-terminal 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 superfamily, betacoronavirus / Non-structural protein 6, betacoronavirus / Betacoronavirus nucleic acid-binding (NAB) / Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus / Non-structural protein NSP3A domain-like superfamily / Papain-like protease, N-terminal domain superfamily, coronavirus / Papain-like viral protease, palm and finger domains, coronavirus / : / Coronavirus (CoV) Nsp2 middle domain profile. / Coronavirus (CoV) Nsp2 N-terminal domain profile. / Coronavirus (CoV) Nsp2 C-terminal domain profile. / NSP1, globular domain, alpha/betacoronavirus / : / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus (CoV) Nsp1 globular domain profile. / Coronavirus replicase NSP2, N-terminal / Nonstructural protein 2, N-terminal domain, coronavirus / Coronavirus replicase NSP2, C-terminal / Non-structural protein 2, C-terminal domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl 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. / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / NSP3, second ubiquitin-like (Ubl) domain, coronavirus
Similarity search - Domain/homology
: / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsAschenbrenner, J.C. / Fearon, D. / Tomlinson, C.W.E. / Marples, P.G. / Fairhead, M. / Balcomb, B.H. / Chandran, A.V. / Godoy, A.S. / Koekemoer, L. / Lithgo, R.M. ...Aschenbrenner, J.C. / Fearon, D. / Tomlinson, C.W.E. / Marples, P.G. / Fairhead, M. / Balcomb, B.H. / Chandran, A.V. / Godoy, A.S. / Koekemoer, L. / Lithgo, R.M. / Ni, X. / Thompson, W. / Wang, S. / Wild, C. / Williams, E.P. / Winokan, M. / Walsh, M.A. / von Delft, F.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19AI171399 United States
CitationJournal: To Be Published
Title: Group deposition of SARS-CoV-2 NSP3 Macrodomain in complex with inhibitors from the ASAP AViDD centre
Authors: Aschenbrenner, J.C. / Fearon, D. / Tomlinson, C.W.E. / Marples, P.G. / Fairhead, M. / Balcomb, B.H. / Chandran, A.V. / Godoy, A.S. / Koekemoer, L. / Lithgo, R.M. / Ni, X. / Thompson, W. / ...Authors: Aschenbrenner, J.C. / Fearon, D. / Tomlinson, C.W.E. / Marples, P.G. / Fairhead, M. / Balcomb, B.H. / Chandran, A.V. / Godoy, A.S. / Koekemoer, L. / Lithgo, R.M. / Ni, X. / Thompson, W. / Wang, S. / Wild, C. / Williams, E.P. / Winokan, M. / Walsh, M.A. / von Delft, F.
History
DepositionJan 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2024Provider: 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 nsp3
B: Papain-like protease nsp3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4124
Polymers36,5522
Non-polymers8612
Water7,891438
1
A: Papain-like protease nsp3
hetero molecules


  • defined by author
  • 18.7 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)18,7062
Polymers18,2761
Non-polymers4301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Papain-like protease nsp3
hetero molecules


  • defined by author
  • 18.7 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)18,7062
Polymers18,2761
Non-polymers4301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.743, 33.276, 120.162
Angle α, β, γ (deg.)90, 94.82, 90
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 18275.771 Da / Num. of mol.: 2
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 (E. coli)
References: UniProt: P0DTD1, ubiquitinyl hydrolase 1, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Chemical ChemComp-A1AMD / (4M)-4-(4-{[(1R)-1-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-6-yl)-2-methylpropyl]amino}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-methyl-1H-pyrazole-5-carbonitrile


Mass: 430.462 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H22N8O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 438 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.11 Å3/Da / Density % sol: 41.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.1 M MES (pH 6.50) and 30 % w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9212 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: Jul 7, 2023
RadiationProtocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9212 Å / Relative weight: 1
ReflectionResolution: 1.5→39.91 Å / Num. obs: 49468 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.086 / Rpim(I) all: 0.036 / Rrim(I) all: 0.094 / Χ2: 0.53 / Net I/σ(I): 11.3 / Num. measured all: 324291
Reflection shellResolution: 1.5→1.53 Å / % possible obs: 98.8 % / Redundancy: 5.2 % / Rmerge(I) obs: 1.668 / Num. measured all: 12310 / Num. unique obs: 2370 / CC1/2: 0.246 / Rpim(I) all: 0.809 / Rrim(I) all: 1.863 / Χ2: 0.15 / Net I/σ(I) obs: 0.4

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Processing

Software
NameVersionClassificationNB
BUSTER2.10.4refinement
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→21.86 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.946 / SU R Cruickshank DPI: 0.084 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.091 / SU Rfree Blow DPI: 0.09 / SU Rfree Cruickshank DPI: 0.085
RfactorNum. reflection% reflectionSelection details
Rfree0.2271 2424 -RANDOM
Rwork0.193 ---
obs0.1947 49217 99.5 %-
Displacement parametersBiso mean: 27.98 Å2
Baniso -1Baniso -2Baniso -3
1-0.3386 Å20 Å24.9826 Å2
2--2.7102 Å20 Å2
3----3.0488 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: LAST / Resolution: 1.5→21.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2528 0 64 438 3030
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012719HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.043708HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d928SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes526HARMONIC5
X-RAY DIFFRACTIONt_it2719HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion342SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2609SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.9
X-RAY DIFFRACTIONt_other_torsion16.33
LS refinement shellResolution: 1.5→1.5 Å
RfactorNum. reflection% reflection
Rfree0.3843 43 -
Rwork0.3905 --
obs0.3902 985 90.7 %
Refinement TLS params.

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)
10.70710.30430.80852.1244-0.01571.29970.0155-0.1714-0.0049-0.1714-0.08480.0307-0.00490.03070.0693-0.00370.00790.03890.02040.0145-0.08679.2845-1.171813.245
21.64490.85320.70241.61860.76231.67880.04340.0107-0.05360.01070.03660.062-0.05360.062-0.080.01310.0080.0198-0.00870.0047-0.092523.151912.2945.2833
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A3 - 170
2X-RAY DIFFRACTION1{ A|* }A475
3X-RAY DIFFRACTION2{ B|* }B4 - 169
4X-RAY DIFFRACTION2{ B|* }B426

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