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- PDB-7sgh: SARS-CoV-2 Main Protease (Mpro) in Complex with ML124N -

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Basic information

Entry
Database: PDB / ID: 7sgh
TitleSARS-CoV-2 Main Protease (Mpro) in Complex with ML124N
Components3C-like proteinase
KeywordsVIRAL PROTEIN / SARSCoV2 / SARS-CoV-2 / coronavirus / Main Protease / Protease / Mpro / 3C-like proteinase / CL3pro / Inhibitor / Complex / Covalent / Adduct / ML124N / Ketoamide / Peptidomimetic
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 / TRAF3-dependent IRF activation pathway / Translation of Replicase and Assembly of the Replication Transcription Complex / 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 endoplasmic reticulum-Golgi intermediate compartment / 3'-5'-RNA exonuclease activity / 5'-3' DNA helicase activity / symbiont-mediated suppression of host NF-kappaB cascade / host cell endosome / 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 / mRNA (guanine-N7)-methyltransferase / omega peptidase activity / methyltransferase cap1 / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity / SARS-CoV-2 modulates host translation machinery / host cell Golgi apparatus / symbiont-mediated perturbation of host ubiquitin-like protein modification / DNA helicase / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / host cell perinuclear region of cytoplasm / single-stranded RNA binding / host cell endoplasmic reticulum membrane / viral protein processing / lyase activity / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / copper ion binding / RNA-directed RNA polymerase / viral translational frameshifting / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / lipid binding / DNA-templated transcription / 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 / Nonstructural protein 15, middle domain, alpha/betacoronavirus / Nonstructural protein 15, N-terminal domain, alpha/beta-coronavirus / NSP14, guanine-N7-methyltransferase domain, coronavirus / : / : / : / Coronavirus Nonstructural protein 13, 1B domain ...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 Nonstructural protein 13, 1B domain / Coronavirus Non-structural protein 13, zinc-binding domain / Coronavirus Nonstructural protein 13, stalk domain / Coronavirus (CoV) guanine-N7-methyltransferase (N7-MTase) domain profile. / Coronavirus (CoV) Nsp15 N-terminal oligomerization domain profile. / Coronavirus Nsp12 Interface domain profile. / NSP12 RNA-dependent RNA polymerase, coronavirus / Coronavirus Nsp12 RNA-dependent RNA polymerase (RdRp) 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 / Nidovirus 2-O-methyltransferase / Coronavirus replicase NSP15, middle domain / Coronavirus replicase NSP15, N-terminal oligomerisation / Nidovirus 2'-O-methyltransferase (2'-O-MTase) domain profile. / Non-structural protein NSP16, coronavirus-like / Non-structural protein 14, coronavirus / RNA polymerase, N-terminal, coronavirus / Nidovirus 3'-5' exoribonuclease domain / Coronavirus 2'-O-methyltransferase / Coronavirus proofreading exoribonuclease / Coronavirus RNA-dependent RNA polymerase, N-terminal / Nidovirus 3'-5' exoribonuclease (ExoN) domain profile. / 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 / 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 / (+) RNA virus helicase core domain / (+)RNA virus helicase core domain profile. / 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 / NSP1, globular domain, alpha/betacoronavirus / Coronavirus (CoV) Nsp2 middle domain profile. / 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 / : / Coronavirus 3Ecto domain profile. / NSP3, second ubiquitin-like (Ubl) domain, coronavirus / Coronavirus Nsp3a Ubl domain profile. / Coronavirus Nsp3d Ubl domain profile. / : / NSP3, first ubiquitin-like (Ubl) domain, coronavirus / Coronavirus (CoV) Nsp3 Y domain profile. / Coronavirus replicase NSP7 / Peptidase family C16 domain profile.
Similarity search - Domain/homology
Chem-99W / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.85 Å
AuthorsWestberg, M. / Fernandez, D. / Lin, M.Z.
Funding support2items
OrganizationGrant numberCountry
Novo Nordisk FoundationNNF18OC0031816
Other private
CitationJournal: To Be Published
Title: Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases
Authors: Westberg, M. / Su, Y. / Zou, X. / Rustagi, A. / Beck, A. / Ning, L. / Fernandez, D. / Blish, C. / Lin, M.Z.
History
DepositionOct 5, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 5, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)137,1248
Polymers135,3024
Non-polymers1,8224
Water9,548530
1
A: 3C-like proteinase
C: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,5624
Polymers67,6512
Non-polymers9112
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3030 Å2
ΔGint-15 kcal/mol
Surface area25160 Å2
MethodPISA
2
B: 3C-like proteinase
D: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,5624
Polymers67,6512
Non-polymers9112
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2930 Å2
ΔGint-11 kcal/mol
Surface area25440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.538, 102.523, 102.487
Angle α, β, γ (deg.)90.000, 91.590, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 33825.547 Da / Num. of mol.: 4
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 B (bacteria) / Strain (production host): T7 Express LysY/Iq
References: UniProt: P0DTD1, SARS coronavirus main proteinase
#2: Chemical
ChemComp-99W / (S)-N-((S)-1-imino-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-4-methyl-2-(2-((2,4,6-trifluorophenyl)amino)acetamido)pentanamide / N-(2,4,6-trifluorophenyl)glycyl-N-{(1Z,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide


Mass: 455.474 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28F3N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 530 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.63 Å3/Da / Density % sol: 53.27 %
Crystal growTemperature: 289.15 K / Method: vapor diffusion, sitting drop
Details: Sitting drops consisted of 0.16 uL A:0.16 uL B: A) 7 mg/mL Mpro + 1 mM ML124N in 20 mM Tris pH 7.3 + 2 mM DTT + 3 % DMSO B) Morpheus HT-96 well D1: 0.1 M MES pH 6.5 + 0.12 M Alcohols + 30 % v/v Precipitant Mix 1

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 31, 2021
Details: Flat Si Rh coated M0, Kirkpatrick-Baez flat bent Si M1 & M2
RadiationMonochromator: Liquid nitrogen-cooled double crystal, non fixed exit slit
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.85→102.447 Å / Num. all: 115016 / Num. obs: 115016 / % possible obs: 96.8 % / Redundancy: 3.6 % / Rpim(I) all: 0.081 / Rrim(I) all: 0.156 / Rsym value: 0.133 / Net I/av σ(I): 3.9 / Net I/σ(I): 5.1 / Num. measured all: 410865
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
1.85-1.953.60.9140.661279170170.5651.0810.9141.798.4
1.95-2.073.50.5550.955732158250.3460.6570.5552.596.6
2.07-2.213.40.3671.647911142910.230.4360.3673.393.2
2.21-2.393.70.2722.351799141620.1650.3190.2724.198.4
2.39-2.623.60.1933.246450128630.1180.2280.1935.197.7
2.62-2.933.50.1443.539417113240.0890.170.1446.494.7
2.93-3.383.80.15.939206104240.0590.1170.18.499
3.38-4.143.50.0766.92979385290.0460.0890.0769.495.7
4.14-5.853.80.0559.72581568510.0320.0640.05510.298.8
5.85-67.5133.60.04411.81346337300.0260.0510.0441096.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
SCALAdata scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6LZE

6lze


Resolution: 1.85→45.89 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.94 / SU B: 4.488 / SU ML: 0.124 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.143 / ESU R Free: 0.135 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2315 5614 4.9 %RANDOM
Rwork0.1948 ---
obs0.1966 109345 96.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 115.58 Å2 / Biso mean: 28.795 Å2 / Biso min: 10.1 Å2
Baniso -1Baniso -2Baniso -3
1--1.76 Å2-0 Å2-0.5 Å2
2---2.08 Å2-0 Å2
3---3.86 Å2
Refinement stepCycle: final / Resolution: 1.85→45.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9423 0 128 531 10082
Biso mean--41.65 35.03 -
Num. residues----1219
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0139905
X-RAY DIFFRACTIONr_bond_other_d0.0010.0159156
X-RAY DIFFRACTIONr_angle_refined_deg1.5841.6413486
X-RAY DIFFRACTIONr_angle_other_deg1.3281.57521051
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.77551249
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.53122.895494
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.587151568
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1791544
X-RAY DIFFRACTIONr_chiral_restr0.0740.21288
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211520
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022356
LS refinement shellResolution: 1.85→1.898 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 426 -
Rwork0.339 8211 -
all-8637 -
obs--98.44 %

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