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Entry
Database: PDB / ID: 5rl0
TitlePanDDA analysis group deposition of computational designs of SARS-CoV-2 main protease covalent inhibitors -- Crystal Structure of SARS-CoV-2 main protease in complex with LON-WEI-adc59df6-2 (Mpro-x3110)
Components3C-like proteinase
KeywordsHYDROLASE/HYDROLASE inhibitor / SGC - Diamond I04-1 fragment screening / PanDDA / XChemExplorer / HYDROLASE-HYDROLASE inhibitor complex
Function / homology
Function and homology information


protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity ...protein guanylyltransferase activity / RNA endonuclease activity producing 3'-phosphomonoesters, hydrolytic mechanism / mRNA guanylyltransferase activity / 5'-3' RNA helicase activity / Lyases; Phosphorus-oxygen lyases / Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC) / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / Maturation of replicase proteins / TRAF3-dependent IRF activation pathway / ISG15-specific peptidase activity / Transcription of SARS-CoV-2 sgRNAs / Translation of Replicase and Assembly of the Replication Transcription Complex / snRNP Assembly / Replication of the SARS-CoV-2 genome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / host cell endoplasmic reticulum-Golgi intermediate compartment / double membrane vesicle viral factory outer membrane / SARS coronavirus main proteinase / 5'-3' DNA helicase activity / 3'-5'-RNA exonuclease activity / host cell endosome / symbiont-mediated degradation of host mRNA / mRNA guanylyltransferase / symbiont-mediated suppression of host ISG15-protein conjugation / G-quadruplex RNA binding / symbiont-mediated suppression of host toll-like receptor signaling pathway / 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 / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / host cell Golgi apparatus / symbiont-mediated suppression of host NF-kappaB cascade / symbiont-mediated perturbation of host ubiquitin-like protein modification / DNA helicase / methyltransferase cap1 activity / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase 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 / lyase activity / 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 / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / lipid binding / 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
main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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. ...main proteinase (3clpro) structure, domain 3 / main proteinase (3clpro) structure, domain 3 / 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 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 / (+) 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. / 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
Similarity search - Domain/homology
Chem-VEG / Replicase polyprotein 1ab
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / molecular replacement / Resolution: 1.69 Å
AuthorsFearon, D. / Owen, C.D. / Douangamath, A. / Lukacik, P. / Powell, A.J. / Strain-Damerell, C.M. / Zaidman, D. / Krojer, T. / Gehrtz, P. / Wild, C. ...Fearon, D. / Owen, C.D. / Douangamath, A. / Lukacik, P. / Powell, A.J. / Strain-Damerell, C.M. / Zaidman, D. / Krojer, T. / Gehrtz, P. / Wild, C. / Aimon, A. / Brandao-Neto, J. / Carbery, A. / Dunnett, L. / Gorrie-Stone, T.J. / Skyner, R. / London, N. / Walsh, M.A. / von Delft, F.
CitationJournal: To Be Published
Title: PanDDA analysis group deposition of computational designs of SARS-CoV-2 main protease covalent inhibitors
Authors: Fearon, D. / Owen, C.D. / Douangamath, A. / Lukacik, P. / Powell, A.J. / Strain-Damerell, C.M. / Zaidman, D. / Krojer, T. / Gehrtz, P. / Wild, C. / Aimon, A. / Brandao-Neto, J. / Carbery, A. ...Authors: Fearon, D. / Owen, C.D. / Douangamath, A. / Lukacik, P. / Powell, A.J. / Strain-Damerell, C.M. / Zaidman, D. / Krojer, T. / Gehrtz, P. / Wild, C. / Aimon, A. / Brandao-Neto, J. / Carbery, A. / Dunnett, L. / Gorrie-Stone, T.J. / Skyner, R. / London, N. / Walsh, M.A. / von Delft, F.
History
DepositionAug 5, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 7, 2021Group: Database references / Structure summary / Category: audit_author / citation_author / Item: _audit_author.name / _citation_author.name
Revision 1.2Dec 25, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_validate_close_contact / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6567
Polymers33,8261
Non-polymers8306
Water5,332296
1
A: 3C-like proteinase
hetero molecules

A: 3C-like proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,31214
Polymers67,6512
Non-polymers1,66012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area4840 Å2
ΔGint2 kcal/mol
Surface area25260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)112.561, 52.771, 44.375
Angle α, β, γ (deg.)90.000, 102.970, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1245-

HOH

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Components

#1: Protein 3C-like proteinase


Mass: 33825.547 Da / Num. of mol.: 1
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, SARS coronavirus main proteinase
#2: Chemical ChemComp-VEG / ethyl N-[(2R)-2-[(4-tert-butylphenyl)(propanoyl)amino]-2-(pyridin-3-yl)acetyl]-beta-alaninate


Mass: 439.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H33N3O4
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 296 / Source method: isolated from a natural source / Formula: H2O
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: 1.9 Å3/Da / Density % sol: 35.21 % / Mosaicity: 0 °
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 15% PEG 4K, 5% DMSO, 0.1M MES pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9126 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9126 Å / Relative weight: 1
ReflectionResolution: 1.69→54.94 Å / Num. obs: 28373 / % possible obs: 99.4 % / Redundancy: 3.5 % / Biso Wilson estimate: 26.76 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.097 / Rpim(I) all: 0.06 / Rrim(I) all: 0.115 / Net I/σ(I): 7.4 / Num. measured all: 98317 / Scaling rejects: 155
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.69-1.7231.433449815040.2960.9661.7360.797.1
8.79-54.943.80.0318332200.9980.0180.03633.299.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTER2.10.3 (20-MAY-2020)refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.23data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6LU7

6lu7


Resolution: 1.69→54.85 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.943 / SU R Cruickshank DPI: 0.118 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.126 / SU Rfree Blow DPI: 0.116 / SU Rfree Cruickshank DPI: 0.112
RfactorNum. reflection% reflectionSelection details
Rfree0.214 1397 4.93 %RANDOM
Rwork0.1774 ---
obs0.1792 28320 99.2 %-
Displacement parametersBiso max: 75.34 Å2 / Biso mean: 29.33 Å2 / Biso min: 16.36 Å2
Baniso -1Baniso -2Baniso -3
1--5.6967 Å20 Å20.6831 Å2
2--1.7452 Å20 Å2
3---3.9514 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 1.69→54.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2347 0 52 296 2695
Biso mean--44.71 40.07 -
Num. residues----304
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d832SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes435HARMONIC5
X-RAY DIFFRACTIONt_it2463HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion315SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2705SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2463HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3344HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3.83
X-RAY DIFFRACTIONt_other_torsion15.46
LS refinement shellResolution: 1.69→1.7 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2615 26 4.59 %
Rwork0.2291 541 -
all-567 -
obs--94.12 %
Refinement TLS params.Method: refined / Origin x: 11.8307 Å / Origin y: 0.5908 Å / Origin z: 5.0711 Å
111213212223313233
T-0.032 Å2-0.0076 Å2-0.0084 Å2--0.0036 Å2-0.0025 Å2---0.0353 Å2
L0.2072 °20.0845 °2-0.0558 °2-1.1244 °2-0.8647 °2--0.7244 °2
S-0.0358 Å °-0.0001 Å °-0.0237 Å °0.0049 Å °0.0196 Å °-0.0493 Å °-0.0203 Å °0.0021 Å °0.0162 Å °
Refinement TLS groupSelection details: { A|* }

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