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- PDB-6ffn: Structure-based design and synthesis of macrocyclic human rhinovi... -

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Basic information

Entry
Database: PDB / ID: 6ffn
TitleStructure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors
Components3C protease
KeywordsHYDROLASE / 3C Protease / Rhinovirus / Inhibitor
Function / homology
Function and homology information


symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / ribonucleoside triphosphate phosphatase activity / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / nucleoside-triphosphate phosphatase ...symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of RIG-I activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / ribonucleoside triphosphate phosphatase activity / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / endocytosis involved in viral entry into host cell / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / DNA replication / RNA helicase activity / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / DNA-templated transcription / host cell nucleus / virion attachment to host cell / structural molecule activity / proteolysis / RNA binding / ATP binding / membrane / metal ion binding
Similarity search - Function
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) / Peptidase C3A/C3B, picornaviral ...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) / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / 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 / Trypsin-like serine proteases / Thrombin, subunit H / 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. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-D8K / Genome polyprotein
Similarity search - Component
Biological speciesHuman rhinovirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsWiesmann, C. / Farady, C.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors.
Authors: Namoto, K. / Sirockin, F. / Sellner, H. / Wiesmann, C. / Villard, F. / Moreau, R.J. / Valeur, E. / Paulding, S.C. / Schleeger, S. / Schipp, K. / Loup, J. / Andrews, L. / Swale, R. / Robinson, M. / Farady, C.J.
History
DepositionJan 8, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 21, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 14, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3C protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,9655
Polymers20,1261
Non-polymers8394
Water4,378243
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area680 Å2
ΔGint-14 kcal/mol
Surface area8400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.459, 77.459, 87.863
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

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Protein , 1 types, 1 molecules A

#1: Protein 3C protease


Mass: 20125.793 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human rhinovirus 2 / Production host: Escherichia coli (E. coli)
References: UniProt: P04936, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C

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Non-polymers , 5 types, 247 molecules

#2: Chemical ChemComp-D8K / ~{N}-[(5~{S},8~{S},11~{S},15~{R})-8-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-2,7,10,14-tetrakis(oxidanylidene)-1,6,9,13-tetrazabicyclo[13.3.0]octadecan-11-yl]-5-methyl-1,2-oxazole-3-carboxamide


Mass: 572.585 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33FN6O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 243 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.78 Å3/Da / Density % sol: 67.47 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 2.0 M Ammonium Sulfate 0.1 M Na Acetate, pH 4.5,

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99988 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jul 25, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99988 Å / Relative weight: 1
ReflectionResolution: 1.75→67.08 Å / Num. obs: 31250 / % possible obs: 100 % / Redundancy: 9.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.126 / Rpim(I) all: 0.043 / Rrim(I) all: 0.133 / Net I/σ(I): 15.4
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all
1.75-2.029.70.669107980.9220.2280.707
3.5-67.089.30.04441090.9990.0150.046

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Processing

Software
NameVersionClassification
Aimless0.3.3data scaling
REFMAC5.8.0071refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2xya

2xya


Resolution: 1.75→20 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.96 / SU B: 3.425 / SU ML: 0.048 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.073 / ESU R Free: 0.073
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1695 1548 5 %RANDOM
Rwork0.149 ---
obs0.1501 29638 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 113.71 Å2 / Biso mean: 23.26 Å2 / Biso min: 6.51 Å2
Baniso -1Baniso -2Baniso -3
1-0.21 Å20.1 Å20 Å2
2--0.21 Å2-0 Å2
3----0.68 Å2
Refinement stepCycle: final / Resolution: 1.75→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1415 0 56 243 1714
Biso mean--31.34 33.68 -
Num. residues----182
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0191509
X-RAY DIFFRACTIONr_bond_other_d0.0010.021403
X-RAY DIFFRACTIONr_angle_refined_deg1.6022.0122047
X-RAY DIFFRACTIONr_angle_other_deg0.8083.0013228
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4995185
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.38624.54566
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.9915248
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.788158
X-RAY DIFFRACTIONr_chiral_restr0.1070.2227
X-RAY DIFFRACTIONr_gen_planes_refined0.0210.0211710
X-RAY DIFFRACTIONr_gen_planes_other0.0170.02329
LS refinement shellResolution: 1.751→1.786 Å / Rfactor Rfree error: 0 / Total num. of bins used: 25
RfactorNum. reflection% reflection
Rfree0.24 97 -
Rwork0.281 1708 -
all-1805 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -34.2299 Å / Origin y: 14.3246 Å / Origin z: -7.1078 Å
111213212223313233
T0.0239 Å2-0.0048 Å2-0.0048 Å2-0.0099 Å2-0.0007 Å2--0.0086 Å2
L0.493 °20.2894 °2-0.222 °2-0.7203 °2-0.2003 °2--1.1604 °2
S0.0104 Å °0.0254 Å °-0.0163 Å °0.0032 Å °-0.0149 Å °-0.0185 Å °0.0642 Å °0.0422 Å °0.0045 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-1 - 180
2X-RAY DIFFRACTION1L1
3X-RAY DIFFRACTION1W2 - 251
4X-RAY DIFFRACTION1B1 - 3

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