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- PDB-7l8h: EV68 3C protease (3Cpro) in Complex with Rupintrivir -

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Basic information

Entry
Database: PDB / ID: 7l8h
TitleEV68 3C protease (3Cpro) in Complex with Rupintrivir
Components3C ProteasePicornain 3C
KeywordsHYDROLASE/INHIBITOR / ENTEROVIRUS / EV68 / PROTEASE / PROTEASE INHIBITOR / COMPLEX / HYDROLASE INHIBITOR COMPLEX / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / RUPINTRIVIR / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


RNA-protein covalent cross-linking / : / : / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / ribonucleoside triphosphate phosphatase activity / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane ...RNA-protein covalent cross-linking / : / : / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / ribonucleoside triphosphate phosphatase activity / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / : / nucleoside-triphosphate phosphatase / protein complex oligomerization / monoatomic ion channel activity / RNA helicase activity / induction by virus of host autophagy / 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 / host cell nucleus / virion attachment to host cell / structural molecule activity / RNA binding / ATP binding / metal ion binding
Similarity search - Function
Picornavirus coat protein VP4 superfamily / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) ...Picornavirus coat protein VP4 superfamily / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-AG7 / Genome polyprotein
Similarity search - Component
Biological speciesHuman enterovirus D68
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsLockbaum, G.J. / Henes, M. / Lee, J.M. / Timm, J. / Nalivaika, E.A. / Yilmaz, N.K. / Thompson, P.R. / Schiffer, C.A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM135919 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R21 AI149716 United States
CitationJournal: Biochemistry / Year: 2021
Title: Pan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode.
Authors: Lockbaum, G.J. / Henes, M. / Lee, J.M. / Timm, J. / Nalivaika, E.A. / Thompson, P.R. / Kurt Yilmaz, N. / Schiffer, C.A.
History
DepositionDec 31, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C Protease
B: 3C Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8054
Polymers41,6032
Non-polymers1,2012
Water5,062281
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3860 Å2
ΔGint-23 kcal/mol
Surface area14860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.900, 80.900, 197.160
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid -4 through -3 or (resid -2...
21(chain B and (resid -4 through 20 or (resid 21...
12chain A and resid 201
22chain B and resid 201

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111SERSERHISHIS(chain A and (resid -4 through -3 or (resid -2...AA-4 - -32 - 3
121METMETALAALA(chain A and (resid -4 through -3 or (resid -2...AA-2 - -14 - 5
131SERSERSERSER(chain A and (resid -4 through -3 or (resid -2...AA-4 - 1802 - 186
141SERSERSERSER(chain A and (resid -4 through -3 or (resid -2...AA-4 - 1802 - 186
151SERSERSERSER(chain A and (resid -4 through -3 or (resid -2...AA-4 - 1802 - 186
161SERSERSERSER(chain A and (resid -4 through -3 or (resid -2...AA-4 - 1802 - 186
211SERSERTHRTHR(chain B and (resid -4 through 20 or (resid 21...BB-4 - 202 - 26
221GLUGLULYSLYS(chain B and (resid -4 through 20 or (resid 21...BB21 - 2227 - 28
231SERSERASPASP(chain B and (resid -4 through 20 or (resid 21...BB-4 - 1812 - 187
241SERSERASPASP(chain B and (resid -4 through 20 or (resid 21...BB-4 - 1812 - 187
251SERSERASPASP(chain B and (resid -4 through 20 or (resid 21...BB-4 - 1812 - 187
261SERSERASPASP(chain B and (resid -4 through 20 or (resid 21...BB-4 - 1812 - 187
112AG7AG7AG7AG7chain CAC201
212AG7AG7AG7AG7chain DBD201

NCS ensembles :
ID
1
2

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Components

#1: Protein 3C Protease / Picornain 3C / Peptidase C3


Mass: 20801.611 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human enterovirus D68 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A2K8BQT2
#2: Chemical ChemComp-AG7 / 4-{2-(4-FLUORO-BENZYL)-6-METHYL-5-[(5-METHYL-ISOXAZOLE-3-CARBONYL)-AMINO]-4-OXO-HEPTANOYLAMINO}-5-(2-OXO-PYRROLIDIN-3-YL)-PENTANOIC ACID ETHYL ESTER / RUPINTRIVIR, bound form / Rupintrivir


Mass: 600.678 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H41FN4O7 / Feature type: SUBJECT OF INVESTIGATION / Comment: antivirus, protease inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 281 / 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: 3.01 Å3/Da / Density % sol: 59.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 15% (w/v) PEG 3350, 0.1 M Bis-Tris-Propane pH 6.5, 0.2 M Potassium Thiocyanate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Dec 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
Reflection twinOperator: h,-h-k,-l / Fraction: 0.39
ReflectionResolution: 1.95→40.45 Å / Num. obs: 34962 / % possible obs: 99.67 % / Redundancy: 4.6 % / CC1/2: 0.996 / Rmerge(I) obs: 0.07731 / Rpim(I) all: 0.04105 / Net I/σ(I): 12.82
Reflection shellResolution: 1.951→2.021 Å / Rmerge(I) obs: 0.6496 / Mean I/σ(I) obs: 3.1 / Num. unique obs: 3510 / CC1/2: 0.903 / Rpim(I) all: 0.3403

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASERphasing
PHENIX1.19_4080refinement
Cootmodel building
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ZV8

3zv8


Resolution: 1.95→40.45 Å / Cross valid method: THROUGHOUT / σ(F): 2.71 / Phase error: 30.47 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.1863 1728 4.94 %
Rwork0.1577 33233 -
obs0.1811 34959 99.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 94.94 Å2 / Biso mean: 38.8942 Å2 / Biso min: 15.44 Å2
Refinement stepCycle: final / Resolution: 1.95→40.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2793 0 166 281 3240
Biso mean--33.46 41.12 -
Num. residues----371
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042945
X-RAY DIFFRACTIONf_angle_d0.6874012
X-RAY DIFFRACTIONf_dihedral_angle_d8.139418
X-RAY DIFFRACTIONf_chiral_restr0.048458
X-RAY DIFFRACTIONf_plane_restr0.004521
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1116X-RAY DIFFRACTION5.009TORSIONAL
12B1116X-RAY DIFFRACTION5.009TORSIONAL
21A16X-RAY DIFFRACTION5.009TORSIONAL
22B16X-RAY DIFFRACTION5.009TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.95-2.010.35321420.33332767290994
2.01-2.070.2871480.27322800294895
2.07-2.150.26731480.24942743289195
2.15-2.230.21611560.23032756291295
2.23-2.340.23091360.22122776291295
2.34-2.460.22991420.21382788293095
2.46-2.610.25531400.21372769290995
2.61-2.810.19281450.20042771291695
2.81-3.10.23341390.18332790292995
3.1-3.540.21871450.17422747289294
3.55-4.460.18711420.14712760290294
4.47-40.450.19131430.13822766290995

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