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

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Entry
Database: PDB / ID: 8uho
TitleCrystal structure of SARS CoV-2 3CL protease in complex with GSK4365096A
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: 2.02 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 9, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 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

Downloads & links

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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)68,8994
Polymers67,6512
Non-polymers1,2472
Water3,513195
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2840 Å2
ΔGint-13 kcal/mol
Surface area24650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.724, 100.404, 103.116
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
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 1 through 45 or (resid 46...
d_2ens_1(chain "B" and (resid 1 through 99 or (resid 100...

NCS domain segments:

Ens-ID: ens_1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11SERSERSERSERAA1 - 3011 - 301
d_12WTEWTEWTEWTEAC401
d_21SERSERSERSERBB1 - 3011 - 301
d_22WTEWTEWTEWTEBD401

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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-WTE / N-[(benzyloxy)carbonyl]-4-fluoro-L-phenylalanyl-N-[(2S,3Z)-1-[(2S)-oxolan-2-yl]-3-(2-oxooxolan-3-ylidene)propan-2-yl]-L-leucinamide / GSK4365096A


Mass: 623.712 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H42FN3O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 195 / 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: 2.59 Å3/Da / Density % sol: 52.53 %
Crystal growTemperature: 295 K / Method: vapor diffusion / pH: 4.6
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 EIGER X 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: 2.02→50 Å / Num. obs: 46504 / % possible obs: 99.5 % / Redundancy: 7.3 % / Biso Wilson estimate: 24.65 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.068 / Net I/σ(I): 27.9
Reflection shellResolution: 2.02→2.05 Å / Rmerge(I) obs: 0.45 / Num. unique obs: 2266 / CC1/2: 0.921

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.02→41.02 Å / SU ML: 0.1775 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.2628
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2166 1998 4.35 %
Rwork0.1843 43983 -
obs0.1857 45981 98.47 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 31.9 Å2
Refinement stepCycle: LAST / Resolution: 2.02→41.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4608 0 90 195 4893
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00734807
X-RAY DIFFRACTIONf_angle_d0.9416542
X-RAY DIFFRACTIONf_chiral_restr0.0501741
X-RAY DIFFRACTIONf_plane_restr0.0176847
X-RAY DIFFRACTIONf_dihedral_angle_d10.3861666
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 0.828299055835 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.02-2.070.27381160.22532762X-RAY DIFFRACTION87.27
2.07-2.130.28071490.20413048X-RAY DIFFRACTION97.08
2.13-2.190.21271460.19033108X-RAY DIFFRACTION99.12
2.19-2.260.24411360.21143126X-RAY DIFFRACTION99.21
2.26-2.340.22691400.19693146X-RAY DIFFRACTION99.61
2.34-2.440.20781440.18443140X-RAY DIFFRACTION99.73
2.44-2.550.24061430.18393128X-RAY DIFFRACTION99.6
2.55-2.680.23221470.19473167X-RAY DIFFRACTION99.1
2.68-2.850.24561410.18953160X-RAY DIFFRACTION99.94
2.85-3.070.23821460.1863196X-RAY DIFFRACTION99.79
3.07-3.380.22471460.18123175X-RAY DIFFRACTION99.58
3.38-3.870.1941460.16743196X-RAY DIFFRACTION99.08
3.87-4.870.19071430.1543255X-RAY DIFFRACTION100
4.87-41.020.19241550.20443376X-RAY DIFFRACTION99.32
Refinement TLS params.Method: refined / Origin x: -2.19848794207 Å / Origin y: -2.79880488156 Å / Origin z: 16.1252760746 Å
111213212223313233
T0.0927854465629 Å2-0.00560463882303 Å20.0136305811837 Å2-0.136713735546 Å2-0.0192834741025 Å2--0.166507575949 Å2
L0.568217219308 °20.0714399269987 °2-0.180946239604 °2-0.460148683518 °2-0.108223388924 °2--2.05469839443 °2
S0.00371786806287 Å °0.0401337427488 Å °-0.0406212702747 Å °-0.0558921882901 Å °-0.0379313923864 Å °-0.0392505453925 Å °0.0368494285096 Å °0.105099404928 Å °0.0238026118316 Å °
Refinement TLS groupSelection details: all

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