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- PDB-7u9y: WDR5 bound to 2-(3,5-dimethoxybenzyl)-7-((2-methyl-1H-imidazol-1-... -

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Basic information

Entry
Database: PDB / ID: 7u9y
TitleWDR5 bound to 2-(3,5-dimethoxybenzyl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one
ComponentsWD repeat-containing protein 5
KeywordsTranscription/Transcription Inhibitor / Transcription-Transcription 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 / HATs acetylate histones / Neddylation / 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 / 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
Similarity search - Domain/homology
BENZAMIDINE / Chem-M4U / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsRietz, T.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)HHSN261200800001E United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization.
Authors: Teuscher, K.B. / Meyers, K.M. / Wei, Q. / Mills, J.J. / Tian, J. / Alvarado, J. / Sai, J. / Van Meveren, M. / South, T.M. / Rietz, T.A. / Zhao, B. / Moore, W.J. / Stott, G.M. / Tansey, W.P. ...Authors: Teuscher, K.B. / Meyers, K.M. / Wei, Q. / Mills, J.J. / Tian, J. / Alvarado, J. / Sai, J. / Van Meveren, M. / South, T.M. / Rietz, T.A. / Zhao, B. / Moore, W.J. / Stott, G.M. / Tansey, W.P. / Lee, T. / Fesik, S.W.
History
DepositionMar 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 27, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: 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 1.2Oct 18, 2023Group: 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: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2493
Polymers33,5891
Non-polymers6602
Water5,477304
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: fluorescence resonance energy transfer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.259, 86.122, 41.094
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 33589.133 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR5, BIG3 / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: P61964
#2: Chemical ChemComp-BEN / BENZAMIDINE


Mass: 120.152 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H8N2
#3: Chemical ChemComp-M4U / (5P)-2-[(3,5-dimethoxyphenyl)methyl]-7-[(2-methyl-1H-imidazol-1-yl)methyl]-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3,4-dihydroisoquinolin-1(2H)-one


Mass: 539.549 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H28F3N5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 304 / 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: 2.14 Å3/Da / Density % sol: 42.54 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: BIS-Tris, ammonium acetate, PEG 3350, benzamidine

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.987 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Feb 25, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. obs: 23402 / % possible obs: 100 % / Redundancy: 8 % / Biso Wilson estimate: 18.92 Å2 / Rmerge(I) obs: 0.099 / Rpim(I) all: 0.037 / Rrim(I) all: 0.106 / Χ2: 1.062 / Net I/σ(I): 7.4 / Num. measured all: 187442
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.937.90.61811300.9180.2330.6620.85399.9
1.93-1.9780.53211600.9120.20.5690.91999.7
1.97-2.0180.48911300.9190.1830.5230.954100
2.01-2.0580.42711630.9330.160.4570.959100
2.05-2.0980.37711420.9560.1410.4031.02199.9
2.09-2.1480.31911580.9720.1190.3411.09799.8
2.14-2.198.10.27511380.9770.1030.2941.097100
2.19-2.258.20.26711540.9770.0990.2861.088100
2.25-2.328.10.23911710.9830.0890.2551.092100
2.32-2.398.10.20811590.9850.0780.2231.09100
2.39-2.488.20.17411420.990.0650.1861.056100
2.48-2.588.10.15511830.9930.0580.1661.109100
2.58-2.78.20.13111580.9930.0490.1391.176100
2.7-2.848.10.11111610.9940.0410.1191.234100
2.84-3.028.10.09311640.9950.0350.11.35100
3.02-3.258.10.0711830.9970.0260.0751.255100
3.25-3.578.10.05211910.9980.020.0561.204100
3.57-4.0980.04112040.9980.0150.0441.042100
4.09-5.157.90.02912180.9990.0110.0310.796100
5.15-307.30.03212930.9990.0130.0350.81799.8

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.20_4459refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3EG6

3eg6


Resolution: 1.9→29.55 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 16.59 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1887 1155 4.96 %
Rwork0.1476 22121 -
obs0.1495 23276 99.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 60.02 Å2 / Biso mean: 20.07 Å2 / Biso min: 8.69 Å2
Refinement stepCycle: final / Resolution: 1.9→29.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2364 0 48 304 2716
Biso mean--16.61 30.14 -
Num. residues----305
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.9-1.990.24011410.18792694283599
1.99-2.090.23661780.1642669284799
2.09-2.220.20371400.149627242864100
2.22-2.40.2091550.155727382893100
2.4-2.640.23421240.159327512875100
2.64-3.020.17541460.151727662912100
3.02-3.80.14991440.133628192963100
3.8-29.550.17121270.136229603087100

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