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

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Basic information

Entry
Database: PDB / ID: 6uif
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 / 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
Chem-Q8P / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.603 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
DepositionSep 30, 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)67,9404
Polymers66,9842
Non-polymers9562
Water10,863603
1
A: WD repeat domain 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9702
Polymers33,4921
Non-polymers4781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: WD repeat domain 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9702
Polymers33,4921
Non-polymers4781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.825, 56.846, 64.786
Angle α, β, γ (deg.)107.930, 91.210, 114.290
Int Tables number1
Space group name H-MP1

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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-Q8P / 4-{[(5-bromo-3-chloro-2-hydroxyphenyl)sulfonyl]amino}-1-cyclopentyl-N-methyl-1H-imidazole-2-carboxamide


Mass: 477.761 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H18BrClN4O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 603 / 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: 2.2 Å3/Da / Density % sol: 44.09 %
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: 0.978 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Jul 26, 2019
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: 69175 / % possible obs: 92.6 % / Redundancy: 2.5 % / CC1/2: 0.988 / Rmerge(I) obs: 0.059 / Rpim(I) all: 0.038 / Rrim(I) all: 0.066 / Rsym value: 0.053 / Net I/σ(I): 25
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.279 / Mean I/σ(I) obs: 4.4 / Num. unique obs: 3243 / CC1/2: 0.837 / Rpim(I) all: 0.143 / Rrim(I) all: 0.235 / Rsym value: 0.185 / % possible all: 86.6

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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: 1.603→27.51 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.99 / Phase error: 18.87
RfactorNum. reflection% reflection
Rfree0.1937 1994 2.88 %
Rwork0.1668 --
obs0.1676 69166 92.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 57.02 Å2 / Biso mean: 16.9654 Å2 / Biso min: 4.69 Å2
Refinement stepCycle: final / Resolution: 1.603→27.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4579 0 54 603 5236
Biso mean--25.3 27.72 -
Num. residues----601
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.6032-1.64330.23271230.1991431282
1.6433-1.68770.25311380.1995454987
1.6877-1.73740.22611350.1938461389
1.7374-1.79350.24941460.1846466590
1.7935-1.85760.20481380.175469791
1.8576-1.93190.20241410.169478192
1.9319-2.01980.17611410.1693486593
2.0198-2.12630.21251430.1706483093
2.1263-2.25940.19731500.1691489594
2.2594-2.43380.19251460.1742492395
2.4338-2.67850.21321440.1759497395
2.6785-3.06570.18461450.1682497096
3.0657-3.86070.17851520.1492504897
3.8607-27.510.16351520.1495505197
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)
11.38190.35080.02251.2804-0.02950.98620.0303-0.17380.1180.1034-0.08350.2039-0.027-0.11910.02340.05780.01570.00880.1004-0.01170.0875-20.0632-19.7059-8.6802
21.4562-0.1349-0.17811.37780.54781.3821-0.01470.04890.09930.00740.1111-0.133-0.00290.1925-0.05960.05490.0058-0.00680.099-0.00450.0638-1.3582-19.5589-16.96
31.93840.2838-0.21540.93110.38491.4922-0.01790.0125-0.33780.0001-0.0309-0.00670.1422-0.0080.03620.12550.0109-0.01080.05430.00380.1079-14.1852-36.6165-16.6553
41.1354-0.02910.23081.141-0.23250.6995-0.04510.1002-0.0788-0.1730.06620.0666-0.03010.012-0.02250.1006-0.0211-0.01040.08510.00760.05761.826-35.158611.8457
51.2380.21680.30681.54170.35450.981-0.0281-0.0499-0.139-0.10760.1737-0.3086-0.00080.1232-0.08310.0613-0.00280.0260.1096-0.02240.134519.5548-35.938119.4003
61.8855-0.3043-0.56041.3422-0.42110.8594-0.018-0.12770.058-0.00470.1487-0.3204-0.12860.1738-0.15230.0812-0.02590.01730.1219-0.06990.162521.7023-24.478221.3778
71.52820.50870.52561.24250.74461.0751-0.097-0.02820.143-0.11580.06850.0146-0.12930.01730.01690.1313-0.01170.00440.0725-0.00680.05865.652-17.95720.1169
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 32 through 125 )A32 - 125
2X-RAY DIFFRACTION2chain 'A' and (resid 126 through 209 )A126 - 209
3X-RAY DIFFRACTION3chain 'A' and (resid 210 through 334 )A210 - 334
4X-RAY DIFFRACTION4chain 'B' and (resid 32 through 125 )B32 - 125
5X-RAY DIFFRACTION5chain 'B' and (resid 126 through 199 )B126 - 199
6X-RAY DIFFRACTION6chain 'B' and (resid 200 through 233 )B200 - 233
7X-RAY DIFFRACTION7chain 'B' and (resid 234 through 334 )B234 - 334

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