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- PDB-6uj4: Discovery of fragment-inspired heterocyclic benzenesulfonmides as... -

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Basic information

Entry
Database: PDB / ID: 6uj4
TitleDiscovery of fragment-inspired heterocyclic benzenesulfonmides as inhibitors of the WDR5-MYC interaction
ComponentsWD repeat domain 5
KeywordsTRANSCRIPTION / WDR5 / MYC / structure-based design / fragment screening
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 / 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 ...WDR5 beta-propeller domain / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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-Q8S / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.53 Å
AuthorsZhao, B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design.
Authors: Chacon Simon, S. / Wang, F. / Thomas, L.R. / Phan, J. / Zhao, B. / Olejniczak, E.T. / Macdonald, J.D. / Shaw, J.G. / Schlund, C. / Payne, W. / Creighton, J. / Stauffer, S.R. / Waterson, A.G. ...Authors: Chacon Simon, S. / Wang, F. / Thomas, L.R. / Phan, J. / Zhao, B. / Olejniczak, E.T. / Macdonald, J.D. / Shaw, J.G. / Schlund, C. / Payne, W. / Creighton, J. / Stauffer, S.R. / Waterson, A.G. / Tansey, W.P. / Fesik, S.W.
History
DepositionOct 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Oct 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

Downloads & links

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Assembly

Deposited unit
A: WD repeat domain 5
B: WD repeat domain 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8544
Polymers66,9842
Non-polymers8692
Water14,988832
1
A: WD repeat domain 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9272
Polymers33,4921
Non-polymers4351
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: WD repeat domain 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9272
Polymers33,4921
Non-polymers4351
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.674, 96.527, 64.944
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein WD repeat domain 5


Mass: 33492.020 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: P61964
#2: Chemical ChemComp-Q8S / 5-bromo-3-chloro-N-(1-cyclopentyl-2-methyl-1H-imidazol-4-yl)-2-hydroxybenzene-1-sulfonamide


Mass: 434.736 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H17BrClN3O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 832 / 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: 2.18 Å3/Da / Density % sol: 43.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: Bis-Tris 6.5, 0.2 M Ammonium acetate, 28% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.978 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Jul 19, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.53→40 Å / Num. obs: 84598 / % possible obs: 97.6 % / Redundancy: 3.9 % / CC1/2: 0.986 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.052 / Rrim(I) all: 0.107 / Rsym value: 0.093 / Net I/σ(I): 14.1
Reflection shellResolution: 1.53→1.56 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.286 / Num. unique obs: 4025 / CC1/2: 0.835 / R split: 2.93 / Rpim(I) all: 0.169 / Rrim(I) all: 0.313 / Rsym value: 0.261 / % possible all: 92.4

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DY7

6dy7


Resolution: 1.53→29.809 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.46 / Phase error: 16.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1775 1998 2.36 %
Rwork0.1543 82512 -
obs0.1549 84510 97.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 44.05 Å2 / Biso mean: 9.505 Å2 / Biso min: 0.24 Å2
Refinement stepCycle: final / Resolution: 1.53→29.809 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4583 0 48 832 5463
Biso mean--17.47 22.57 -
Num. residues----600
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.53-1.56830.27051360.2064561793
1.5683-1.61070.22581390.1853571795
1.6107-1.65810.20321400.1715580396
1.6581-1.71160.19991360.1652580197
1.7116-1.77270.19391410.1621583497
1.7727-1.84370.19851410.151588298
1.8437-1.92760.15221440.1418589998
1.9276-2.02920.16811430.1454594998
2.0292-2.15630.181480.1447594899
2.1563-2.32270.17811440.1481597599
2.3227-2.55640.16011480.1515597599
2.5564-2.9260.17351460.1564603299
2.926-3.68540.14221510.1406598899
3.6854-29.80.15051410.1406609299
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)
10.0520.00390.01380.0691-0.01750.0854-0.01690.0328-0.0173-0.03920.0072-0.02920.01440.0395-0.06790.0177-0.0090.01650.0401-0.01390.013410.538921.453-8.5755
20.16780.04360.0490.11940.01470.2844-0.0194-0.01970.0241-0.01040.0030.0225-0.0292-0.022-0.00080.0017-0.0022-0.00940.0214-0.00660.004-7.531826.9872-0.9019
30.9326-0.48160.14730.40410.02250.1881-0.0056-0.0329-0.14390.0170.01930.07870.0498-0.03310.00230.0185-0.0017-0.00180.03780.00640.0618-13.819613.2073-2.3435
40.49340.021-0.12220.3746-0.05420.2384-0.01-0.0439-0.12790.00630.00160.05690.04280.01270.00920.05020.00080.00950.01590.00390.04882.23247.2898-5.1194
50.1-0.0264-0.04950.1139-0.03420.2583-0.035-0.05230.02160.0470.0319-0.0258-0.00920.0391-0.18250.01580.0135-0.0030.0349-0.02620.0055-15.434521.9847-30.7544
60.2742-0.06370.00280.4427-0.0930.4472-0.0073-0.0162-0.02220.03970.0144-0.03280.041-0.00170.01950.0188-0.00490.00470.0026-0.00870.0095-23.389510.2468-35.789
70.15860.0284-0.09710.1463-0.06340.3305-0.00930.0206-0.00590.00850.01460.05440.0159-0.04060.0369-0.0052-0.00570.00660.01050.00250.0116-36.294422.0744-38.4081
80.18220.04080.03840.3176-0.05280.20690.00110.00880.09850.01390.0090.1378-0.0392-0.0364-0.03570.0233-0.00030.00380.01550.00550.067-34.331139.0928-36.6555
90.4189-0.03280.26440.3633-0.16280.4564-0.02270.06280.05090.0053-0.0125-0.02190.01840.1172-0.04970.04720.013-0.01120.0374-0.00740.0261-17.777637.5207-32.4976
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 31 through 84 )A31 - 84
2X-RAY DIFFRACTION2chain 'A' and (resid 85 through 199 )A85 - 199
3X-RAY DIFFRACTION3chain 'A' and (resid 200 through 233 )A200 - 233
4X-RAY DIFFRACTION4chain 'A' and (resid 234 through 334 )A234 - 334
5X-RAY DIFFRACTION5chain 'B' and (resid 32 through 106 )B32 - 106
6X-RAY DIFFRACTION6chain 'B' and (resid 107 through 126 )B107 - 126
7X-RAY DIFFRACTION7chain 'B' and (resid 127 through 209 )B127 - 209
8X-RAY DIFFRACTION8chain 'B' and (resid 210 through 253 )B210 - 253
9X-RAY DIFFRACTION9chain 'B' and (resid 254 through 334 )B254 - 334

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