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

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Basic information

Entry
Database: PDB / ID: 6ujh
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
(2R)-2-(4-chlorophenyl)-3-oxobutanenitrile / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.493 Å
AuthorsPhan, J. / Fesik, S.W.
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
B: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,69210
Polymers68,7822
Non-polymers9108
Water16,556919
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7774
Polymers34,3911
Non-polymers3863
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)34,9156
Polymers34,3911
Non-polymers5245
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.135, 47.274, 68.542
Angle α, β, γ (deg.)89.980, 90.500, 104.350
Int Tables number1
Space group name H-MP1

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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.: 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-QBS / (2R)-2-(4-chlorophenyl)-3-oxobutanenitrile


Mass: 193.630 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H8ClNO / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 919 / 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: 2.15 Å3/Da / Density meas: 73 Mg/m3 / Density % sol: 42.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / 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: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Nov 25, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.493→50 Å / Num. obs: 87702 / % possible obs: 94.7 % / Redundancy: 2.3 % / Rmerge(I) obs: 0.059 / Rpim(I) all: 0.048 / Rrim(I) all: 0.077 / Net I/σ(I): 12.46
Reflection shellResolution: 1.5→1.53 Å / Rmerge(I) obs: 0.27 / Mean I/σ(I) obs: 3.15 / Num. unique obs: 4131 / Rpim(I) all: 0.22 / Rrim(I) all: 0.35 / Χ2: 1.03

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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: 1.493→27.462 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 17.63
RfactorNum. reflection% reflection
Rfree0.1685 8987 10.25 %
Rwork0.146 --
obs0.1483 87682 94.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 81.16 Å2 / Biso mean: 18.5134 Å2 / Biso min: 5.94 Å2
Refinement stepCycle: final / Resolution: 1.493→27.462 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4840 0 53 920 5813
Biso mean--23.31 31.44 -
Num. residues----626
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065288
X-RAY DIFFRACTIONf_angle_d1.2227225
X-RAY DIFFRACTIONf_chiral_restr0.09802
X-RAY DIFFRACTIONf_plane_restr0.009912
X-RAY DIFFRACTIONf_dihedral_angle_d12.1591893
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.4932-1.51020.24752290.2228206775
1.5102-1.52790.23972740.2027254789
1.5279-1.54660.21342760.2015253692
1.5466-1.56610.21732730.1787256691
1.5661-1.58670.19712690.1729256092
1.5867-1.60850.20412770.1645261993
1.6085-1.63150.18382540.161260891
1.6315-1.65580.20933030.1617256994
1.6558-1.68170.18872970.1553256392
1.6817-1.70920.18253440.1541257594
1.7092-1.73870.19773410.1633257094
1.7387-1.77030.19982960.1576262394
1.7703-1.80440.17983120.1564261794
1.8044-1.84120.1763060.1437258594
1.8412-1.88120.17262860.1492268794
1.8812-1.9250.17812830.14265596
1.925-1.97310.17033340.1389263995
1.9731-2.02640.16052710.1447270197
2.0264-2.0860.16043170.1425263995
2.086-2.15330.17273040.1407268696
2.1533-2.23030.1863320.1443265797
2.2303-2.31950.17413610.1458266597
2.3195-2.4250.17643320.15266297
2.425-2.55280.17252930.1546272097
2.5528-2.71260.15583420.1519269698
2.7126-2.92180.15723170.1458271598
2.9218-3.21550.15622520.1439279998
3.2155-3.67980.1362990.1235271998
3.6798-4.63250.13863130.123276698
4.6325-5.58520.16143000.142268496
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)
10.5054-0.3233-0.20450.66580.35771.30560.0267-0.07540.0358-0.0060.0537-0.0618-0.24040.0891-0.05960.1184-0.0081-0.00750.0822-0.01070.095431.20851.4967-2.6818
20.9472-0.1079-0.1531.32990.26151.2096-0.041-0.0056-0.08210.13860.0764-0.09070.11570.0613-0.02880.10580.0187-0.01610.058-0.00580.086733.0652-16.9825-11.4966
31.5311-0.0633-0.04810.8688-0.14391.82790.01970.0306-0.25870.0257-0.08410.1440.3729-0.24110.07520.1791-0.02860.00470.1235-0.01980.172117.5738-19.4297-4.9899
40.83240.1136-0.18461.21390.69881.16150.02830.0177-0.0289-0.1204-0.14380.1636-0.1324-0.25820.08930.10560.0293-0.01530.1697-0.02960.122516.1447-1.9919-2.0658
50.3710.267-0.02360.717-0.13660.7897-0.00820.11710.0228-0.05110.0599-0.0147-0.1306-0.0666-0.06790.0892-0.00920.01360.09720.01370.097328.3819-20.391219.7307
60.9127-0.3520.07720.9092-0.22450.98080.01840.0008-0.07550.02640.01760.06060.1136-0.0588-0.03020.0903-0.02220.00660.06340.0050.091627.4565-38.050831.8729
70.8255-0.09170.01291.1782-0.30371.10030.01490.0144-0.01240.0299-0.0191-0.1264-0.01660.10560.01040.0743-0.02320.01020.09660.00390.100341.9944-25.704323.8266
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 22 through 125 )A22 - 125
2X-RAY DIFFRACTION2chain 'A' and (resid 126 through 209 )A126 - 209
3X-RAY DIFFRACTION3chain 'A' and (resid 210 through 252 )A210 - 252
4X-RAY DIFFRACTION4chain 'A' and (resid 253 through 334 )A253 - 334
5X-RAY DIFFRACTION5chain 'B' and (resid 22 through 83 )B22 - 83
6X-RAY DIFFRACTION6chain 'B' and (resid 84 through 209 )B84 - 209
7X-RAY DIFFRACTION7chain 'B' and (resid 210 through 334 )B210 - 334

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