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- PDB-6ufx: WD repeat-containing protein 5 complexed with N-[(3,5-dimethoxyph... -

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Basic information

Entry
Database: PDB / ID: 6ufx
TitleWD repeat-containing protein 5 complexed with N-[(3,5-dimethoxyphenyl)methyl]-4'-fluoro-5-{[(2E)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl]methyl}-2'-methyl[1,1'-biphenyl]-3-carboxamide (compound 13)
ComponentsWD repeat-containing protein 5
KeywordsGENE REGULATION/INHIBITOR / inhibitor / GENE REGULATION-INHIBITOR complex
Function / homology
Function and homology information


histone H3Q5ser reader activity / histone H3K4me1 reader activity / Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity / Cardiogenesis ...histone H3Q5ser reader activity / histone H3K4me1 reader activity / Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity / Cardiogenesis / Formation of WDR5-containing histone-modifying complexes / histone methyltransferase complex / regulation of cell division / MLL1 complex / regulation of embryonic development / histone acetyltransferase complex / positive regulation of gluconeogenesis / transcription initiation-coupled chromatin remodeling / gluconeogenesis / skeletal system development / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / PKMTs methylate histone lysines / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / mitotic spindle / Neddylation / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / histone binding / regulation of cell cycle / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
WDR5 beta-propeller domain / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / WD domain, G-beta repeat / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. ...WDR5 beta-propeller domain / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / WD domain, G-beta repeat / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-Q6S / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.015 Å
AuthorsRietz, T.A. / Fesik, S.W. / Zhao, B.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)HHSN261200800001E United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA200709 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA68485 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
Authors: Tian, J. / Teuscher, K.B. / Aho, E.R. / Alvarado, J.R. / Mills, J.J. / Meyers, K.M. / Gogliotti, R.D. / Han, C. / Macdonald, J.D. / Sai, J. / Shaw, J.G. / Sensintaffar, J.L. / Zhao, B. / ...Authors: Tian, J. / Teuscher, K.B. / Aho, E.R. / Alvarado, J.R. / Mills, J.J. / Meyers, K.M. / Gogliotti, R.D. / Han, C. / Macdonald, J.D. / Sai, J. / Shaw, J.G. / Sensintaffar, J.L. / Zhao, B. / Rietz, T.A. / Thomas, L.R. / Payne, W.G. / Moore, W.J. / Stott, G.M. / Kondo, J. / Inoue, M. / Coffey, R.J. / Tansey, W.P. / Stauffer, S.R. / Lee, T. / Fesik, S.W.
History
DepositionSep 25, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation.year ..._citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Feb 5, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 11, 2023Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8392
Polymers33,3511
Non-polymers4891
Water2,540141
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area10880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.625, 98.896, 80.546
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-526-

HOH

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Components

#1: Protein WD repeat-containing protein 5 / BMP2-induced 3-kb gene protein


Mass: 33350.789 Da / Num. of mol.: 1 / Fragment: UNP residues 32-334
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR5, BIG3 / Production host: Escherichia coli (E. coli) / References: UniProt: P61964
#2: Chemical ChemComp-Q6S / N-[(3,5-dimethoxyphenyl)methyl]-4'-fluoro-5-{[(2E)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl]methyl}-2'-methyl[1,1'-biphenyl]-3-carboxamide


Mass: 488.553 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H29FN4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 141 / 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: 2.35 Å3/Da / Density % sol: 47.6 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Bis-Tris or HEPES or Tris-HCl, pH 6.0-8.0, 0.2 M ammonium acetate, 20-30% PEG3350
PH range: 6.0-8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.987 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Apr 10, 2019
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. obs: 20876 / % possible obs: 100 % / Redundancy: 12.1 % / CC1/2: 0.998 / Rmerge(I) obs: 0.162 / Rpim(I) all: 0.048 / Rrim(I) all: 0.169 / Rsym value: 0.108 / Net I/σ(I): 19.6
Reflection shellResolution: 2→2.03 Å / Rmerge(I) obs: 1.035 / Mean I/σ(I) obs: 3.41 / Num. unique obs: 1005 / CC1/2: 0.762 / Rpim(I) all: 0.319 / Rrim(I) all: 1.085 / Rsym value: 1.032

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3EG6

3eg6


Resolution: 2.015→28.746 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.09
RfactorNum. reflection% reflection
Rfree0.2083 1040 4.99 %
Rwork0.1691 --
obs0.171 20848 98.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 68.56 Å2 / Biso mean: 23.091 Å2 / Biso min: 10.9 Å2
Refinement stepCycle: final / Resolution: 2.015→28.746 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2267 0 36 141 2444
Biso mean--23.51 30.83 -
Num. residues----303
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.015-2.12110.27881440.206258192
2.1211-2.25390.24281350.18972849100
2.2539-2.42790.24631460.18662819100
2.4279-2.6720.22481640.18262827100
2.672-3.05830.20381600.16992831100
3.0583-3.85170.19991270.15372914100
3.8517-28.7460.17371640.15652987100

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