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- PDB-8ujy: Crystal structure of human WD repeat-containing protein 5 in comp... -

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Basic information

Entry
Database: PDB / ID: 8ujy
TitleCrystal structure of human WD repeat-containing protein 5 in complex with 4-(3,5-dimethoxybenzyl)-9-(4-fluoro-2-methylphenyl)-7-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (compound 8)
ComponentsWD repeat-containing protein 5
KeywordsTRANSCRIPTION / WDR5 / Cancer / Drug Discovery
Function / homology
Function and homology information


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 ...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
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
Similarity search - Domain/homology
Chem-VV3 / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.01 Å
AuthorsZhao, B. / Amporndanai, K. / Fesik, S.W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)HHSN261200800001E United States
CitationJournal: J.Med.Chem. / Year: 2023
Title: Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors.
Authors: Teuscher, K.B. / Mills, J.J. / Tian, J. / Han, C. / Meyers, K.M. / Sai, J. / South, T.M. / Crow, M.M. / Van Meveren, M. / Sensintaffar, J.L. / Zhao, B. / Amporndanai, K. / Moore, W.J. / ...Authors: Teuscher, K.B. / Mills, J.J. / Tian, J. / Han, C. / Meyers, K.M. / Sai, J. / South, T.M. / Crow, M.M. / Van Meveren, M. / Sensintaffar, J.L. / Zhao, B. / Amporndanai, K. / Moore, W.J. / Stott, G.M. / Tansey, W.P. / Lee, T. / Fesik, S.W.
History
DepositionOct 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 20, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jan 10, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)69,6414
Polymers68,5802
Non-polymers1,0612
Water8,647480
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.810, 47.680, 68.869
Angle α, β, γ (deg.)88.040, 89.270, 74.660
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21A

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / End auth comp-ID: ASP / End label comp-ID: ASP / Auth asym-ID: A / Label asym-ID: A / Auth seq-ID: 32 - 333 / Label seq-ID: 10 - 311

Dom-ID
1
2

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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Components

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


Mass: 34289.887 Da / Num. of mol.: 2 / Fragment: UNP residues 23-334
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-VV3 / (9P)-4-[(3,5-dimethoxyphenyl)methyl]-9-(4-fluoro-2-methylphenyl)-7-{[(2E)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl]methyl}-3,4-dihydro-1,4-benzoxazepin-5(2H)-one


Mass: 530.590 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H31FN4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 480 / 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: 2.21 Å3/Da / Density % sol: 44.3 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1 M Bis-Tris pH 7.0, 0.2 M ammonium acetate, 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Mar 23, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.01→28.658 Å / Num. obs: 34546 / % possible obs: 90.4 % / Redundancy: 3.9 % / CC1/2: 0.996 / Rmerge(I) obs: 0.079 / Rpim(I) all: 0.079 / Rrim(I) all: 0.112 / Net I/σ(I): 7
Reflection shellResolution: 2.01→2.06 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.321 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 2725 / CC1/2: 0.885 / Rpim(I) all: 0.321 / Rrim(I) all: 0.46 / % possible all: 95.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
iMOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.01→28.658 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.913 / SU B: 5.735 / SU ML: 0.151 / Cross valid method: FREE R-VALUE / ESU R: 0.263 / ESU R Free: 0.196
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2322 1714 4.962 %
Rwork0.1884 32831 -
all0.191 --
obs-34545 90.387 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 22.378 Å2
Baniso -1Baniso -2Baniso -3
1--0.913 Å2-0.302 Å20.306 Å2
2--2.28 Å2-0.024 Å2
3----1.87 Å2
Refinement stepCycle: LAST / Resolution: 2.01→28.658 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4658 0 78 480 5216
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0124856
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164431
X-RAY DIFFRACTIONr_angle_refined_deg1.5321.7856615
X-RAY DIFFRACTIONr_angle_other_deg0.5261.75110237
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.2225607
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.07914.1323
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg16.927204
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.80510757
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.22310182
X-RAY DIFFRACTIONr_chiral_restr0.0730.2741
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025648
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021060
X-RAY DIFFRACTIONr_nbd_refined0.190.2852
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2020.24225
X-RAY DIFFRACTIONr_nbtor_refined0.1770.22332
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0880.22511
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2370.2429
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0570.23
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2320.29
X-RAY DIFFRACTIONr_nbd_other0.2120.254
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.250.212
X-RAY DIFFRACTIONr_mcbond_it2.4732.372439
X-RAY DIFFRACTIONr_mcbond_other2.4732.3722440
X-RAY DIFFRACTIONr_mcangle_it3.794.2383042
X-RAY DIFFRACTIONr_mcangle_other3.794.243043
X-RAY DIFFRACTIONr_scbond_it2.512.6242417
X-RAY DIFFRACTIONr_scbond_other2.512.6252418
X-RAY DIFFRACTIONr_scangle_it3.8724.7373573
X-RAY DIFFRACTIONr_scangle_other3.8714.7383574
X-RAY DIFFRACTIONr_lrange_it7.02829.48322254
X-RAY DIFFRACTIONr_lrange_other6.84529.121789
X-RAY DIFFRACTIONr_ncsr_local_group_10.0890.059898
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.088730.05009
12AX-RAY DIFFRACTIONLocal ncs0.088730.05009
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.01-2.0620.3211440.26225650.26528280.9330.94695.79210.248
2.062-2.1180.292830.24717600.24927420.9380.95467.21370.236
2.118-2.1790.2641190.25524520.25626760.9480.95396.07620.242
2.179-2.2460.2781180.24323680.24425820.9470.95896.2820.229
2.246-2.3190.267820.2215200.22224900.9520.96664.33730.206
2.319-2.40.2351080.22722630.22724500.9590.96496.77550.216
2.4-2.490.261170.21321540.21523500.9510.9796.63830.199
2.49-2.5910.317870.22321050.22722670.9430.96796.69170.213
2.591-2.7050.3361040.20916130.21721400.9310.97180.23360.201
2.705-2.8360.253920.18319260.18620830.9590.97896.87950.179
2.836-2.9870.227900.18218270.18419700.9710.97997.30960.181
2.987-3.1660.2211030.17717280.1818800.9690.9897.39360.18
3.166-3.3820.237670.16716380.1717480.9620.98397.540.174
3.382-3.6490.182590.16513200.16616280.9760.98584.70520.176
3.649-3.9910.172490.16111020.16115050.9810.98576.47840.175
3.991-4.4510.188870.13612550.13913660.9810.9998.2430.155
4.451-5.1190.143550.11711150.11811930.9890.99298.07210.143
5.119-6.220.209400.1619720.16310290.9760.98798.34790.189
6.22-8.5960.2720.1817090.1837950.9740.98398.2390.215
8.596-28.6580.205380.1794390.184860.9710.98698.14810.251

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