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

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Basic information

Entry
Database: PDB / ID: 6uik
TitleDiscovery of fragment-inspired heterocyclic benzenesulfonmides as inhibitors of the WDR5-MYC interaction
ComponentsWD repeat domanin 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-Q8M / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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 1, 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 domanin 5
B: WD repeat domanin 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8254
Polymers66,9842
Non-polymers8412
Water14,196788
1
A: WD repeat domanin 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9132
Polymers33,4921
Non-polymers4211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: WD repeat domanin 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9132
Polymers33,4921
Non-polymers4211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)134.263, 46.880, 112.842
Angle α, β, γ (deg.)90.000, 117.390, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein WD repeat domanin 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-Q8M / 5-bromo-3-chloro-N-(1-cyclopentyl-1H-imidazol-4-yl)-2-hydroxybenzene-1-sulfonamide


Mass: 420.709 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H15BrClN3O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 788 / 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: 47.74 %
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: Mar 23, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.6→40 Å / Num. obs: 80531 / % possible obs: 97.5 % / Redundancy: 6.6 % / CC1/2: 0.997 / Rmerge(I) obs: 0.056 / Rpim(I) all: 0.025 / Rrim(I) all: 0.066 / Rsym value: 0.061 / Net I/σ(I): 43.1
Reflection shellResolution: 1.6→1.63 Å / Rmerge(I) obs: 0.22 / Mean I/σ(I) obs: 8.6 / Num. unique obs: 3949 / CC1/2: 0.97 / Rpim(I) all: 0.089 / Rrim(I) all: 0.224 / Rsym value: 0.205 / % possible all: 95.9

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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: 6DY7

6dy7


Resolution: 1.6→28.979 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.46 / Phase error: 17.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1825 1999 2.48 %
Rwork0.1592 78496 -
obs0.1598 80495 97.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 65.63 Å2 / Biso mean: 18.8052 Å2 / Biso min: 5.59 Å2
Refinement stepCycle: final / Resolution: 1.6→28.979 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4662 0 46 788 5496
Biso mean--27.48 31.94 -
Num. residues----607
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.6001-1.64010.21291380.166539494
1.6401-1.68440.19681400.1634550596
1.6844-1.7340.19381410.1585556196
1.734-1.790.18551390.1568547797
1.79-1.85390.19971410.1557552897
1.8539-1.92810.19081420.1557558797
1.9281-2.01590.1931420.1519556797
2.0159-2.12210.17521430.1584561998
2.1221-2.2550.17151440.1618562498
2.255-2.42910.17831420.1653563498
2.4291-2.67330.1891460.1712567698
2.6733-3.05980.17811440.169570799
3.0598-3.85360.18681480.1521576099
3.8536-28.970.16571490.1531585798
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)
11.21460.00590.15640.628-0.41011.3772-0.06390.08780.2515-0.02420.01250.0694-0.2492-0.02630.00680.13720.0019-0.03430.05770.01130.1381127.208322.207234.6343
22.3518-0.50140.59491.6833-0.62062.0692-0.0512-0.32810.15740.02540.0550.2285-0.1625-0.3336-0.0240.10650.01810.00540.1237-0.01470.1126121.829114.668846.669
32.0546-0.24090.48251.2557-0.13211.9994-0.0062-0.0368-0.21530.0258-0.01510.04970.17470.01210.01160.0984-0.00020.00820.04010.00860.1052131.35933.690642.3862
43.86281.52490.56531.6108-0.03951.99780.04440.093-0.4819-0.0334-0.0053-0.05310.41680.19540.04230.21580.0509-0.01020.0828-0.01270.196138.9966-3.551338.3074
53.41840.40240.49672.19850.3382.33070.03630.2683-0.3752-0.19780.0219-0.21680.21320.3729-0.05010.13610.03180.01710.1574-0.01020.1443143.16743.933530.6794
63.0954-0.0480.91031.0606-0.33942.0297-0.00490.2695-0.011-0.1043-0.1006-0.11870.03560.33310.13730.0860.01510.02080.20150.02590.1101144.198311.435426.9629
72.6839-0.15550.63821.1807-0.38872.0033-0.1690.52460.5511-0.1728-0.0886-0.213-0.2260.37030.0630.1309-0.0367-0.01240.28750.10260.1811144.403719.73421.6132
83.01340.13580.36041.0556-0.74090.7259-0.29940.10060.71660.03330.0764-0.1196-0.34630.18540.23740.15320.0091-0.06640.12460.00380.2306134.259823.968126.4964
91.02310.2594-0.19970.88070.13840.94640.0277-0.0975-0.09540.0202-0.0554-0.1184-0.04670.09760.02590.0661-0.0094-0.00230.07460.03890.0904113.8355-8.361911.7682
100.5322-0.75890.32131.98630.23831.6097-0.0636-0.2396-0.44890.0243-0.06490.070.2006-0.13610.02490.1076-0.02410.03910.1260.05740.2181100.8814-21.804516.1598
112.03860.574-0.15660.95650.05421.12250.1267-0.3031-0.01030.1861-0.18560.0564-0.0363-0.04950.02060.1092-0.04380.01940.17430.02670.0672100.0697-5.49224.2624
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 32 through 106 )A32 - 106
2X-RAY DIFFRACTION2chain 'A' and (resid 107 through 126 )A107 - 126
3X-RAY DIFFRACTION3chain 'A' and (resid 127 through 190 )A127 - 190
4X-RAY DIFFRACTION4chain 'A' and (resid 191 through 209 )A191 - 209
5X-RAY DIFFRACTION5chain 'A' and (resid 210 through 233 )A210 - 233
6X-RAY DIFFRACTION6chain 'A' and (resid 234 through 282 )A234 - 282
7X-RAY DIFFRACTION7chain 'A' and (resid 283 through 303 )A283 - 303
8X-RAY DIFFRACTION8chain 'A' and (resid 304 through 334 )A304 - 334
9X-RAY DIFFRACTION9chain 'B' and (resid 31 through 190 )B31 - 190
10X-RAY DIFFRACTION10chain 'B' and (resid 191 through 233 )B191 - 233
11X-RAY DIFFRACTION11chain 'B' and (resid 234 through 334 )B234 - 334

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