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

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Basic information

Entry
Database: PDB / ID: 6ujj
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


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 / Formation of WDR5-containing histone-modifying complexes ...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 / Formation of WDR5-containing histone-modifying complexes / regulation of cell division / regulation of embryonic development / MLL1 complex / histone acetyltransferase complex / positive regulation of gluconeogenesis / methylated histone binding / transcription initiation-coupled chromatin remodeling / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats ...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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
5-[4-(trifluoromethyl)phenyl]-1H-tetrazole / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.731 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)34,6052
Polymers34,3911
Non-polymers2141
Water5,260292
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.482, 86.534, 39.746
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-765-

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-QBP / 5-[4-(trifluoromethyl)phenyl]-1H-tetrazole


Mass: 214.147 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H5F3N4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 292 / 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: 2.04 Å3/Da / Density % sol: 39.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Hepes, 0.2 M ammonium acetate, 32% PEG3350 / PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 1 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: 1 Å / Relative weight: 1
ReflectionResolution: 1.73→50 Å / Num. obs: 29896 / % possible obs: 99.8 % / Redundancy: 7.6 % / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.023 / Rrim(I) all: 0.065 / Χ2: 0.987 / Net I/σ(I): 22.88
Reflection shellResolution: 1.73→1.76 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.68 / Mean I/σ(I) obs: 3.48 / Num. unique obs: 1446 / Rpim(I) all: 0.258 / Rrim(I) all: 0.729 / Χ2: 1.09 / % possible all: 99.4

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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: 1.731→38.214 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 19.21
RfactorNum. reflection% reflection
Rfree0.1895 1510 5.06 %
Rwork0.1553 --
obs0.157 29845 99.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 93.45 Å2 / Biso mean: 29.3612 Å2 / Biso min: 12.45 Å2
Refinement stepCycle: final / Resolution: 1.731→38.214 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2364 0 15 292 2671
Biso mean--75.34 37.59 -
Num. residues----305
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082467
X-RAY DIFFRACTIONf_angle_d1.0753356
X-RAY DIFFRACTIONf_chiral_restr0.05378
X-RAY DIFFRACTIONf_plane_restr0.005416
X-RAY DIFFRACTIONf_dihedral_angle_d11.812878
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.7311-1.7870.26421370.2064238395
1.787-1.85080.23161420.19082530100
1.8508-1.92490.20821470.17272537100
1.9249-2.01250.20671220.16192573100
2.0125-2.11860.19621300.16162558100
2.1186-2.25130.20871110.16212587100
2.2513-2.42510.22481260.17042591100
2.4251-2.66910.22311630.17752585100
2.6691-3.05520.18651660.16752588100
3.0552-3.84870.17051390.14812624100
3.8487-4.64220.15351270.1282277999
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)
12.29070.2405-0.31351.4474-0.87511.22670.05910.1436-0.1729-0.0393-0.0467-0.20230.08480.1959-0.00360.1761-0.0014-0.01910.1869-0.03690.1774-0.288625.7228-11.404
23.16170.5628-0.08711.43550.14291.13590.0729-0.10560.44590.07820.01940.1105-0.1117-0.085-0.06510.1821-0.01830.00580.1307-0.0190.1983-16.015736.9815-8.4738
32.07960.3869-0.40761.7394-0.75841.8814-0.124-0.0013-0.08-0.02350.15970.19530.0258-0.1913-0.03660.1737-0.03130.01570.2486-0.00130.1661-27.816125.0208-7.3167
42.8982-0.74390.53931.7088-0.12831.32280.0058-0.2082-0.9816-0.04130.18040.2530.2899-0.3048-0.06530.2302-0.03920.01060.20180.03060.3657-18.35613.138-6.5233
51.65510.12410.05961.2068-0.07112.13880.01770.091-0.7166-0.11440.03860.11370.30220.2199-0.04360.19760.0421-0.02540.1202-0.06490.3164-3.960313.8005-9.0587
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 30 through 83 )A30 - 83
2X-RAY DIFFRACTION2chain 'A' and (resid 84 through 167 )A84 - 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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