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- PDB-6ujl: Discovery of fragment-inspired heterocyclic benzenesulfonamides a... -

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Basic information

Entry
Database: PDB / ID: 6ujl
TitleDiscovery of fragment-inspired heterocyclic benzenesulfonamides as inhibitors of the WDR5-MYC interaction
ComponentsWD repeat-containing protein 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 / Activation of anterior HOX genes in hindbrain development during early embryogenesis / RMTs methylate histone arginines / 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 / 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
6-methyl-3-(propylsulfanyl)-1,2,4-triazin-5-ol / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.599 Å
AuthorsPhan, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI) 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 3, 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-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7613
Polymers34,3911
Non-polymers3702
Water5,747319
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.190, 86.122, 40.711
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-722-

HOH

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Components

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


Mass: 34390.992 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-QBM / 6-methyl-3-(propylsulfanyl)-1,2,4-triazin-5-ol


Mass: 185.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H11N3OS / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 319 / 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: 2.07 Å3/Da / Density % sol: 40.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Hepes, 0.2 M ammonium acetate, 32% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 12, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 36383 / % possible obs: 94.5 % / Redundancy: 7.3 % / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.026 / Rrim(I) all: 0.074 / Χ2: 0.955 / Net I/σ(I): 17.42
Reflection shellResolution: 1.6→1.63 Å / Rmerge(I) obs: 0.768 / Mean I/σ(I) obs: 3.58 / Num. unique obs: 1866 / Rpim(I) all: 0.297 / Rrim(I) all: 0.825

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHENIXdev_1839refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Y7R

4y7r


Resolution: 1.599→29.583 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.12
RfactorNum. reflection% reflection
Rfree0.1828 1700 4.68 %
Rwork0.165 --
obs0.1658 36351 94.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 81.78 Å2 / Biso mean: 25.4939 Å2 / Biso min: 10.99 Å2
Refinement stepCycle: final / Resolution: 1.599→29.583 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2364 0 24 321 2709
Biso mean--39.6 38.68 -
Num. residues----305
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042496
X-RAY DIFFRACTIONf_angle_d0.9143395
X-RAY DIFFRACTIONf_chiral_restr0.037380
X-RAY DIFFRACTIONf_plane_restr0.004422
X-RAY DIFFRACTIONf_dihedral_angle_d12.014888
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.5991-1.64610.25391670.2236284095
1.6461-1.69930.25931810.2037289798
1.6993-1.760.20131390.1871295298
1.76-1.83050.22741360.174298698
1.8305-1.91370.18721340.1827290095
1.9137-2.01460.2081270.1825297798
2.0146-2.14080.2131460.1689300798
2.1408-2.3060.1615760.1793243979
2.306-2.5380.2011480.1782306699
2.538-2.9050.20921430.17323084100
2.905-3.65890.17641520.154272388
3.6589-4.41280.13891510.1375278085
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)
11.58610.0452-0.5550.7193-0.55060.97590.01290.03240.0104-0.0406-0.0161-0.19050.06590.1391-0.01010.1629-0.00390.00350.1357-0.01550.1503-0.119925.7952-11.384
21.56320.354-0.08160.9984-0.13120.60690.0488-0.03050.33050.04170.03140.0649-0.0806-0.07850.00270.1576-0.0140.00980.1386-0.02240.1793-16.144336.5099-8.6799
30.82290.4965-0.56890.5036-0.04780.3516-0.0405-0.0078-0.0883-0.0460.09120.07050.0212-0.10060.00020.1435-0.01680.00860.21280.00090.1456-27.329824.3656-7.2819
41.42980.07080.08291.39110.09970.436-0.0188-0.22-0.3369-0.03670.0660.17530.1831-0.20630.00340.1706-0.03290.0120.19780.02030.2136-18.021112.7914-6.1171
51.1534-0.3901-0.21940.6532-0.42770.72-0.0617-0.0972-0.2755-0.12450.07-0.04610.13820.1003-0.00090.18960.00160.01430.1197-0.00290.1838-3.428813.7042-8.7795
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 30 through 84 )A30 - 84
2X-RAY DIFFRACTION2chain 'A' and (resid 85 through 167 )A85 - 167
3X-RAY DIFFRACTION3chain 'A' and (resid 168 through 209 )A168 - 209
4X-RAY DIFFRACTION4chain 'A' and (resid 210 through 282 )A210 - 282
5X-RAY DIFFRACTION5chain 'A' and (resid 283 through 334 )A283 - 334

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