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- PDB-6zc6: Small-molecule inhibitors of the PDZ domain of Dishevelled protei... -

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Basic information

Entry
Database: PDB / ID: 6zc6
TitleSmall-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling
ComponentsSegment polarity protein dishevelled homolog DVL-3
KeywordsPEPTIDE BINDING PROTEIN / PDZ / DVL / Inhibitors / Wnt / signalling
Function / homology
Function and homology information


Negative regulation of TCF-dependent signaling by DVL-interacting proteins / positive regulation of neuron projection arborization / non-canonical Wnt signaling pathway / WNT5:FZD7-mediated leishmania damping / frizzled binding / PCP/CE pathway / WNT mediated activation of DVL / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Wnt signaling pathway, planar cell polarity pathway / positive regulation of GTPase activity ...Negative regulation of TCF-dependent signaling by DVL-interacting proteins / positive regulation of neuron projection arborization / non-canonical Wnt signaling pathway / WNT5:FZD7-mediated leishmania damping / frizzled binding / PCP/CE pathway / WNT mediated activation of DVL / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Wnt signaling pathway, planar cell polarity pathway / positive regulation of GTPase activity / canonical Wnt signaling pathway / TCF dependent signaling in response to WNT / regulation of actin cytoskeleton organization / positive regulation of JNK cascade / Degradation of DVL / RHO GTPases Activate Formins / beta-catenin binding / small GTPase binding / regulation of protein localization / protease binding / intracellular signal transduction / protein stabilization / response to xenobiotic stimulus / signaling receptor binding / chromatin / positive regulation of DNA-templated transcription / positive regulation of transcription by RNA polymerase II / cytosol
Similarity search - Function
Dishevelled-3 / Dishevelled protein domain / Dishevelled family / Dishevelled C-terminal / Dishevelled specific domain / Segment polarity protein dishevelled (Dsh) C terminal / Dishevelled-related protein / DIX domain / DIX domain superfamily / DIX domain ...Dishevelled-3 / Dishevelled protein domain / Dishevelled family / Dishevelled C-terminal / Dishevelled specific domain / Segment polarity protein dishevelled (Dsh) C terminal / Dishevelled-related protein / DIX domain / DIX domain superfamily / DIX domain / DIX domain profile. / Domain present in Dishevelled and axin / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / PDZ domain / PDZ domain profile. / Domain present in PSD-95, Dlg, and ZO-1/2. / PDZ domain / PDZ superfamily / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Chem-QEN / Segment polarity protein dishevelled homolog DVL-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.58 Å
AuthorsRoske, Y. / Heinemann, U. / Oschkinat, H.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)806 Germany
CitationJournal: J.Magn.Reson. / Year: 2021
Title: Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling
Authors: Roske, Y. / Heinemann, U. / Oschkinat, H. / Kamdem, N. / Kovalskyy, D. / Platonov, M.O. / Balinskyi, O.M. / Kreuchwig, A. / Saupe, J. / Fang, L. / Diehl, A. / Schmieder, P. / Krause, G. / ...Authors: Roske, Y. / Heinemann, U. / Oschkinat, H. / Kamdem, N. / Kovalskyy, D. / Platonov, M.O. / Balinskyi, O.M. / Kreuchwig, A. / Saupe, J. / Fang, L. / Diehl, A. / Schmieder, P. / Krause, G. / Rademann, J. / Birchmeier, W.
History
DepositionJun 9, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 20, 2022Group: Database references / Category: citation / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 24, 2024Group: 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

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Assembly

Deposited unit
A: Segment polarity protein dishevelled homolog DVL-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,1986
Polymers10,2001
Non-polymers9995
Water1,856103
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area500 Å2
ΔGint5 kcal/mol
Surface area5760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.608, 78.608, 77.818
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number97
Space group name H-MI422
Components on special symmetry positions
IDModelComponents
11A-514-

HOH

21A-595-

HOH

31A-599-

HOH

41A-600-

HOH

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Components

#1: Protein Segment polarity protein dishevelled homolog DVL-3 / Dishevelled-3 / DSH homolog 3


Mass: 10199.681 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DVL3, KIAA0208 / Production host: Escherichia coli (E. coli) / References: UniProt: Q92997
#2: Chemical ChemComp-QEN / 5-bromanyl-2-(naphthalen-2-ylsulfonylamino)benzoic acid


Mass: 406.250 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H12BrNO4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / 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: 2.95 Å3/Da / Density % sol: 58.26 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 1 M ammonium sulphate, 1% PEG 3350, 0.1 M Bis-Tris pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 26, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.58→32.04 Å / Num. obs: 16954 / % possible obs: 99.5 % / Redundancy: 7.1 % / Rrim(I) all: 0.0064 / Net I/σ(I): 18.1
Reflection shellResolution: 1.58→1.62 Å / Mean I/σ(I) obs: 2.9 / Num. unique obs: 1229 / Rrim(I) all: 0.069

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2F0A

2f0a


Resolution: 1.58→32.04 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.956 / SU B: 3.628 / SU ML: 0.055 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.085 / ESU R Free: 0.073 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.198 848 5 %RANDOM
Rwork0.1696 ---
obs0.171 16106 99.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 67.91 Å2 / Biso mean: 22.926 Å2 / Biso min: 12.27 Å2
Baniso -1Baniso -2Baniso -3
1--0.88 Å20 Å2-0 Å2
2---0.88 Å20 Å2
3---1.75 Å2
Refinement stepCycle: final / Resolution: 1.58→32.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms671 0 60 103 834
Biso mean--26.06 40.06 -
Num. residues----90
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0010.014738
X-RAY DIFFRACTIONr_bond_other_d0.0010.017695
X-RAY DIFFRACTIONr_angle_refined_deg0.9691.734996
X-RAY DIFFRACTIONr_angle_other_deg0.9791.5981585
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.929588
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.06925.35728
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.02615122
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.072152
X-RAY DIFFRACTIONr_chiral_restr0.0260.298
X-RAY DIFFRACTIONr_gen_planes_refined0.0190.02805
X-RAY DIFFRACTIONr_gen_planes_other0.0170.02117
X-RAY DIFFRACTIONr_rigid_bond_restr0.59131432
LS refinement shellResolution: 1.58→1.621 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.258 61 -
Rwork0.251 1167 -
all-1228 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 4.4442 Å / Origin y: 19.7734 Å / Origin z: -22.4614 Å
111213212223313233
T0.0289 Å2-0.012 Å2-0.0127 Å2-0.0376 Å20.0088 Å2--0.023 Å2
L1.0913 °20.4473 °20.1107 °2-1.4376 °2-0.3664 °2--0.1872 °2
S-0.0479 Å °0.0916 Å °0.0866 Å °-0.0422 Å °0.0548 Å °0.0289 Å °0.0332 Å °-0.0199 Å °-0.0069 Å °

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