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- PDB-6u5m: Discovery and optimization of salicyclic acid-derived sulfonamide... -

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Basic information

Entry
Database: PDB / ID: 6u5m
TitleDiscovery and optimization of salicyclic acid-derived sulfonamide inhibitors of the WDR5:MYC protein-protein interaction
ComponentsWD repeat-containing protein 5
KeywordsTRANSCRIPTION / WDR5 / MYC / RBBP5 / structure-based design / high-throughput screening
Function / homology
Function and homology information


MLL3/4 complex / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity / : / Cardiogenesis / histone methyltransferase complex / regulation of tubulin deacetylation ...MLL3/4 complex / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity / : / Cardiogenesis / histone methyltransferase complex / regulation of tubulin deacetylation / regulation of cell division / Formation of WDR5-containing histone-modifying complexes / MLL1 complex / regulation of embryonic development / histone acetyltransferase complex / positive regulation of gluconeogenesis / transcription initiation-coupled chromatin remodeling / methylated histone binding / skeletal system development / gluconeogenesis / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / mitotic spindle / PKMTs methylate histone lysines / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Neddylation / HATs acetylate histones / 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
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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. ...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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-Q0S / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsZhao, B. / Wang, F.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction.
Authors: Macdonald, J.D. / Chacon Simon, S. / Han, C. / Wang, F. / Shaw, J.G. / Howes, J.E. / Sai, J. / Yuh, J.P. / Camper, D. / Alicie, B.M. / Alvarado, J. / Nikhar, S. / Payne, W. / Aho, E.R. / ...Authors: Macdonald, J.D. / Chacon Simon, S. / Han, C. / Wang, F. / Shaw, J.G. / Howes, J.E. / Sai, J. / Yuh, J.P. / Camper, D. / Alicie, B.M. / Alvarado, J. / Nikhar, S. / Payne, W. / Aho, E.R. / Bauer, J.A. / Zhao, B. / Phan, J. / Thomas, L.R. / Rossanese, O.W. / Tansey, W.P. / Waterson, A.G. / Stauffer, S.R. / Fesik, S.W.
History
DepositionAug 28, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jan 8, 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

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)68,0494
Polymers66,9842
Non-polymers1,0652
Water13,061725
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0242
Polymers33,4921
Non-polymers5321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0242
Polymers33,4921
Non-polymers5321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)134.390, 46.672, 112.517
Angle α, β, γ (deg.)90.000, 117.300, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 33492.020 Da / Num. of mol.: 2
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-Q0S / 5-bromo-2-hydroxy-N-[3-(methylsulfonyl)-5-(pentafluoro-lambda~6~-sulfanyl)phenyl]benzene-1-sulfonamide


Mass: 532.321 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H11BrF5NO5S3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 725 / 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: 47.63 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: Bis-Tris, ammonium acetate, 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: 0.9787 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Nov 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 1.8→40 Å / Num. obs: 54881 / % possible obs: 94.7 % / Redundancy: 3.8 % / CC1/2: 0.928 / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.056 / Rrim(I) all: 0.119 / Rsym value: 0.104 / Net I/σ(I): 12.3
Reflection shellResolution: 1.8→1.83 Å / Redundancy: 3 % / Rmerge(I) obs: 0.535 / Num. unique obs: 2611 / CC1/2: 0.546 / Rpim(I) all: 0.243 / Rrim(I) all: 0.476 / Rsym value: 0.406 / % possible all: 91

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DY7

6dy7


Resolution: 1.8→29.854 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.44 / Phase error: 17.14 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1857 2000 3.65 %
Rwork0.1626 52828 -
obs0.1634 54828 94.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 73.56 Å2 / Biso mean: 17.4275 Å2 / Biso min: 3.91 Å2
Refinement stepCycle: final / Resolution: 1.8→29.854 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4629 0 56 725 5410
Biso mean--40.82 30.31 -
Num. residues----606
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.8-1.8450.27351360.2498357491
1.845-1.89490.2551360.2277360891
1.8949-1.95070.23351380.206362392
1.9507-2.01360.22081380.1889368393
2.0136-2.08560.20611420.1813372094
2.0856-2.1690.2161400.1693371794
2.169-2.26770.22411420.1693374495
2.2677-2.38720.20351420.1689376995
2.3872-2.53670.20511450.1676382296
2.5367-2.73250.19161450.1606384296
2.7325-3.00720.1641450.1571381696
3.0072-3.44180.1461490.1413393398
3.4418-4.33420.13751490.1229397398
4.3342-29.850.15611530.1412400497
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)
11.2169-0.23-0.34891.0703-0.22620.85160.00430.0842-0.1172-0.0254-0.0240.125-0.001-0.09930.03560.06250.0009-0.01530.0609-0.0350.0695128.974914.271838.217
20.56820.48520.2122.2318-0.12512.0551-0.05950.3371-0.6754-0.0468-0.1843-0.16030.21590.3984-0.19230.11040.05240.04910.0094-0.1260.2401141.59961.001233.8532
31.706-0.2777-0.06430.8546-0.02291.18140.0810.2778-0.0171-0.1471-0.1095-0.046-0.05560.0260.01290.08530.04840.00690.1448-0.01990.0541142.757617.399925.9007
41.0433-0.16050.02020.7860.50390.7302-0.0774-0.1090.58050.09380.0919-0.2362-0.31-0.0243-0.02970.17950.0172-0.08270.0416-0.06880.1819115.024847.204317.8627
52.1716-0.59940.55031.4452-0.12441.6479-0.02480.0410.2245-0.0116-0.0154-0.07220.00930.03680.04820.0805-0.0012-0.02460.04370.00550.0872117.365338.04399.1928
62.31920.27620.24621.7559-0.15311.9211-0.06760.18510.0267-0.07470.0238-0.1041-0.06290.11740.03330.06810.00970.00590.0495-0.00320.0499116.890833.14445.4216
71.74760.2123-0.20941.44980.05381.4406-0.07030.0508-0.3271-0.0374-0.0009-0.06860.16360.083-0.00130.0990.01250.00680.047-0.0180.0927110.444424.50058.1043
83.8624-1.30960.46731.66760.01761.540.003-0.0695-0.4268-0.08510.04180.07980.3937-0.0731-0.00230.1988-0.0309-0.0320.07080.00580.1856103.976618.964411.7813
93.08250.0202-0.63070.99460.03460.64670.0574-0.2333-0.36630.12430.07130.24970.1736-0.2975-0.03910.11450.0096-0.00140.14180.020.1121100.158826.810319.4393
102.142-0.82020.24931.22840.09442.52030.0876-0.3676-0.46270.0798-0.00380.37560.3871-0.34830.04030.0987-0.0150.02630.24420.05320.175496.490626.001824.0381
112.4029-0.03130.32781.0520.62641.4255-0.1498-0.21470.25760.06410.0030.0706-0.1979-0.33670.15870.09160.0335-0.01160.164-0.03280.1017100.513939.256522.097
121.75790.07660.68811.0251-0.02531.2807-0.2402-0.57390.53690.19050.03680.1965-0.3336-0.39820.06090.14650.125-0.02820.2798-0.09240.13998.652342.362628.3514
132.419-0.0270.0430.79370.64330.5231-0.35-0.22310.71350.05480.1110.0065-0.399-0.14940.14010.17250.0298-0.0890.1105-0.04980.2287108.741246.415423.2548
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 31 through 190 )A31 - 190
2X-RAY DIFFRACTION2chain 'A' and (resid 191 through 233 )A191 - 233
3X-RAY DIFFRACTION3chain 'A' and (resid 234 through 334 )A234 - 334
4X-RAY DIFFRACTION4chain 'B' and (resid 31 through 84 )B31 - 84
5X-RAY DIFFRACTION5chain 'B' and (resid 85 through 106 )B85 - 106
6X-RAY DIFFRACTION6chain 'B' and (resid 107 through 148 )B107 - 148
7X-RAY DIFFRACTION7chain 'B' and (resid 149 through 190 )B149 - 190
8X-RAY DIFFRACTION8chain 'B' and (resid 191 through 209 )B191 - 209
9X-RAY DIFFRACTION9chain 'B' and (resid 210 through 233 )B210 - 233
10X-RAY DIFFRACTION10chain 'B' and (resid 234 through 253 )B234 - 253
11X-RAY DIFFRACTION11chain 'B' and (resid 254 through 282 )B254 - 282
12X-RAY DIFFRACTION12chain 'B' and (resid 283 through 303 )B283 - 303
13X-RAY DIFFRACTION13chain 'B' and (resid 304 through 334 )B304 - 334

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