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- PDB-8uia: Crystal structure of SARS CoV-2 3CL protease in complex with GSK4... -

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Basic information

Entry
Database: PDB / ID: 8uia
TitleCrystal structure of SARS CoV-2 3CL protease in complex with GSK4365097A
Components3C-like proteinase nsp5
KeywordsHYDROLASE / 3CL protease / SARS / viral protein
Function / homology
Function and homology information


viral genome replication / methyltransferase 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 / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase ...viral genome replication / methyltransferase 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 / Replication of the SARS-CoV-2 genome / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / endonuclease activity / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / methylation / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / omega peptidase activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / single-stranded RNA binding / regulation of autophagy / host cell perinuclear region of cytoplasm / viral protein processing / host cell endoplasmic reticulum membrane / 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 / lipid binding / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / proteolysis / zinc ion binding / membrane
Similarity search - Function
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. ...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. / 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 / 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
Similarity search - Domain/homology
: / Replicase polyprotein 1a
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsConcha, N.O. / Williams, S.P.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Bioorg.Med.Chem. / Year: 2024
Title: Exploration of the P1 residue in 3CL protease inhibitors leading to the discovery of a 2-tetrahydrofuran P1 replacement.
Authors: Barton, L.S. / Callahan, J.F. / Cantizani, J. / Concha, N.O. / Cotillo Torrejon, I. / Goodwin, N.C. / Joshi-Pangu, A. / Kiesow, T.J. / McAtee, J.J. / Mellinger, M. / Nixon, C.J. / Padron- ...Authors: Barton, L.S. / Callahan, J.F. / Cantizani, J. / Concha, N.O. / Cotillo Torrejon, I. / Goodwin, N.C. / Joshi-Pangu, A. / Kiesow, T.J. / McAtee, J.J. / Mellinger, M. / Nixon, C.J. / Padron-Barthe, L. / Patterson, J.R. / Pearson, N.D. / Pouliot, J.J. / Rendina, A.R. / Buitrago Santanilla, A. / Schneck, J.L. / Sanz, O. / Thalji, R.K. / Ward, P. / Williams, S.P. / King, B.W.
History
DepositionOct 10, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 14, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 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

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Assembly

Deposited unit
A: 3C-like proteinase nsp5
B: 3C-like proteinase nsp5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,1227
Polymers67,6512
Non-polymers1,4715
Water7,026390
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3310 Å2
ΔGint-22 kcal/mol
Surface area24460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.655, 99.263, 103.092
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein 3C-like proteinase nsp5 / 3CL-PRO / 3CLp / Main protease / Mpro / Non-structural protein 5 / nsp5 / SARS coronavirus main proteinase


Mass: 33825.547 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Production host: Escherichia coli (E. coli)
References: UniProt: P0DTC1, SARS coronavirus main proteinase
#2: Chemical ChemComp-WTV / N-[(benzyloxy)carbonyl]-4-fluoro-L-phenylalanyl-N-{(2R)-1-[(2R)-oxolan-2-yl]-3-[(3R)-2-oxooxolan-3-yl]propan-2-yl}-L-leucinamide


Mass: 625.727 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H44FN3O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 390 / 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: 2.56 Å3/Da / Density % sol: 51.92 %
Crystal growTemperature: 295 K / Method: vapor diffusion
Details: 0.02M CaCl2, 30% MPD, 01 M sodium acetate, pH 4.6 Crystals grew over night with seeding and were left to grow for up to two days before they were harvested

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Mar 31, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. obs: 69712 / % possible obs: 98.6 % / Redundancy: 7.4 % / Biso Wilson estimate: 16.89 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.024 / Rrim(I) all: 0.065 / Net I/σ(I): 16.6
Reflection shellResolution: 1.75→1.78 Å / Rmerge(I) obs: 0.318 / Num. unique obs: 3329 / CC1/2: 0.969 / Rpim(I) all: 0.127 / Rrim(I) all: 0.343

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→37.9 Å / SU ML: 0.1598 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.0553
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1936 3570 2.88 %
Rwork0.171 120214 -
obs0.1717 68993 91.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.08 Å2
Refinement stepCycle: LAST / Resolution: 1.75→37.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4576 0 103 390 5069
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00654811
X-RAY DIFFRACTIONf_angle_d0.92926557
X-RAY DIFFRACTIONf_chiral_restr0.0524748
X-RAY DIFFRACTIONf_plane_restr0.0065846
X-RAY DIFFRACTIONf_dihedral_angle_d9.3794681
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.770.23561020.22163121X-RAY DIFFRACTION61.27
1.77-1.80.19991040.20693622X-RAY DIFFRACTION72.43
1.8-1.820.22041150.2083903X-RAY DIFFRACTION76.53
1.82-1.850.22761050.19243990X-RAY DIFFRACTION79.5
1.85-1.880.19141420.18434207X-RAY DIFFRACTION82.96
1.88-1.910.19841180.17844299X-RAY DIFFRACTION84.52
1.91-1.940.19891530.17634369X-RAY DIFFRACTION87.75
1.94-1.980.19941180.17184485X-RAY DIFFRACTION88.54
1.98-2.020.21171170.17534555X-RAY DIFFRACTION90.26
2.02-2.060.20841480.17784683X-RAY DIFFRACTION92.46
2.06-2.10.18321460.18444720X-RAY DIFFRACTION93.85
2.1-2.150.21871270.18344794X-RAY DIFFRACTION94.51
2.15-2.210.20131350.1764637X-RAY DIFFRACTION92.43
2.21-2.270.23421600.17774981X-RAY DIFFRACTION98.41
2.27-2.330.231500.18275054X-RAY DIFFRACTION99.41
2.33-2.410.23641550.17724984X-RAY DIFFRACTION99.4
2.41-2.490.23141480.18384978X-RAY DIFFRACTION99.19
2.49-2.590.19291480.1835037X-RAY DIFFRACTION99.23
2.59-2.710.20541440.18364974X-RAY DIFFRACTION98.96
2.71-2.850.19661620.18245000X-RAY DIFFRACTION98.57
2.85-3.030.23421250.18294958X-RAY DIFFRACTION98.2
3.03-3.270.1811460.17114828X-RAY DIFFRACTION96.15
3.27-3.60.16591540.15755059X-RAY DIFFRACTION99.89
3.6-4.110.16321590.14585025X-RAY DIFFRACTION99.88
4.11-5.180.1551480.14095028X-RAY DIFFRACTION99.18
5.18-37.90.18531410.16954923X-RAY DIFFRACTION97.76
Refinement TLS params.Method: refined / Origin x: -2.17264066204 Å / Origin y: -2.66889997875 Å / Origin z: 16.6236679726 Å
111213212223313233
T0.07129765833 Å20.00016712922275 Å2-0.00134747798117 Å2-0.0865206328803 Å2-0.012748334963 Å2--0.119614557217 Å2
L0.580127840146 °20.0311657631607 °2-0.24294051244 °2-0.214886153586 °20.0319417990645 °2--1.52320544925 °2
S0.0453305810653 Å °0.0179337811657 Å °-0.0249377808584 Å °-0.0302517323461 Å °-0.0308048751534 Å °-5.40451978225E-5 Å °-0.0146270269419 Å °0.0889319090753 Å °-0.00625710086117 Å °
Refinement TLS groupSelection details: all

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