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- PDB-6zc8: Small-molecule inhibitors of the PDZ domain of Dishevelled protei... -

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Basic information

Entry
Database: PDB / ID: 6zc8
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-QEK / Segment polarity protein dishevelled homolog DVL-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.76 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 10, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)21,3974
Polymers20,3992
Non-polymers9982
Water52229
1
A: Segment polarity protein dishevelled homolog DVL-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)10,6992
Polymers10,2001
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Segment polarity protein dishevelled homolog DVL-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)10,6992
Polymers10,2001
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.345, 89.345, 131.659
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number181
Space group name H-MP6422

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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.: 2
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-QEK / 2-[[3-chloranyl-4-[(1~{H}-indazol-3-ylcarbonylamino)methyl]phenyl]sulfonylamino]-5-methyl-benzoic acid


Mass: 498.939 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H19ClN4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / 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: 3.72 Å3/Da / Density % sol: 66.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 1.5 M ammonium sulphate, 12% glycerol, 0.1 M Tris-HCl pH 8.5

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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 22, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.76→33.35 Å / Num. obs: 8495 / % possible obs: 99.9 % / Redundancy: 12.6 % / Rrim(I) all: 0.0142 / Net I/σ(I): 21.4
Reflection shellResolution: 2.76→2.83 Å / Mean I/σ(I) obs: 4.1 / Num. unique obs: 607 / Rrim(I) all: 0.0826

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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: 2.76→33.35 Å / Cor.coef. Fo:Fc: 0.901 / Cor.coef. Fo:Fc free: 0.878 / SU B: 31.276 / SU ML: 0.275 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.335 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2848 425 5 %RANDOM
Rwork0.2444 ---
obs0.2465 8069 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 193.51 Å2 / Biso mean: 43.802 Å2 / Biso min: 24.35 Å2
Baniso -1Baniso -2Baniso -3
1-1.02 Å20.51 Å20 Å2
2--1.02 Å2-0 Å2
3----3.3 Å2
Refinement stepCycle: final / Resolution: 2.76→33.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1320 0 68 29 1417
Biso mean--49.9 42.99 -
Num. residues----176
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0131406
X-RAY DIFFRACTIONr_bond_other_d0.0050.0181329
X-RAY DIFFRACTIONr_angle_refined_deg1.0831.7051905
X-RAY DIFFRACTIONr_angle_other_deg1.2041.623071
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8975172
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.93824.33360
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.93815241
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.074156
X-RAY DIFFRACTIONr_chiral_restr0.0380.2189
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021566
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02262
X-RAY DIFFRACTIONr_rigid_bond_restr0.3132732
LS refinement shellResolution: 2.76→2.831 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 30 -
Rwork0.278 571 -
all-601 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.80230.26650.47471.4444-0.86632.9996-0.0073-0.12740.1222-0.0409-0.0224-0.0073-0.1974-0.04310.02970.132-0.01180.01430.0648-0.0180.009442.7089-17.560710.9531
22.99231.3915-0.59992.8013-0.42743.131-0.05760.08060.11840.01030.0788-0.03750.1525-0.6197-0.02120.0355-0.01560.01180.17080.01070.01824.5808-26.2882-1.559
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A243 - 336
2X-RAY DIFFRACTION2B246 - 336

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