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- PDB-6e23: Displacement of WDR5 from chromatin by a pharmacological WIN site... -

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Basic information

Entry
Database: PDB / ID: 6.0E+23
TitleDisplacement of WDR5 from chromatin by a pharmacological WIN site inhibitor with picomolar affinity
ComponentsWD repeat-containing protein 5
Keywordsgene regulation/inhibitor / WDR5 / WIN-site / fragment screening / structure-based design / mixed-lineage leukemia / DNA BINDING PROTEIN / dna binding protein-inhibitor complex / GENE REGULATION / gene regulation-inhibitor complex
Function / homology
Function and homology information


Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / regulation of tubulin deacetylation / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity / Cardiogenesis / histone methyltransferase complex ...Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / regulation of tubulin deacetylation / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity / Cardiogenesis / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / regulation of cell division / regulation of embryonic development / MLL1 complex / histone acetyltransferase complex / : / positive regulation of gluconeogenesis / transcription initiation-coupled chromatin remodeling / skeletal system development / gluconeogenesis / 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
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 / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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. / WD domain, G-beta repeat / 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-HLJ / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsPhan, J. / Fesik, S.W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)WDR5-MLL1 NExT Leidos Biomedical Research 16X117 HHSN2162008000 01E UNIV 57992 United States
CitationJournal: Cell Rep / Year: 2019
Title: Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.
Authors: Aho, E.R. / Wang, J. / Gogliotti, R.D. / Howard, G.C. / Phan, J. / Acharya, P. / Macdonald, J.D. / Cheng, K. / Lorey, S.L. / Lu, B. / Wenzel, S. / Foshage, A.M. / Alvarado, J. / Wang, F. / ...Authors: Aho, E.R. / Wang, J. / Gogliotti, R.D. / Howard, G.C. / Phan, J. / Acharya, P. / Macdonald, J.D. / Cheng, K. / Lorey, S.L. / Lu, B. / Wenzel, S. / Foshage, A.M. / Alvarado, J. / Wang, F. / Shaw, J.G. / Zhao, B. / Weissmiller, A.M. / Thomas, L.R. / Vakoc, C.R. / Hall, M.D. / Hiebert, S.W. / Liu, Q. / Stauffer, S.R. / Fesik, S.W. / Tansey, W.P.
History
DepositionJul 10, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
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)70,0175
Polymers68,7822
Non-polymers1,2353
Water9,602533
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8892
Polymers34,3911
Non-polymers4981
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)35,1283
Polymers34,3911
Non-polymers7372
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.888, 54.215, 64.517
Angle α, β, γ (deg.)70.19, 88.80, 74.41
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 (E. coli) / References: UniProt: P61964
#2: Chemical ChemComp-HLJ / N-[(3,4-dichlorophenyl)methyl]-3-(6-fluoro-2-methylpyridin-3-yl)-5-{[(2E)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl]methyl}benzamide


Mass: 498.379 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H22Cl2FN5O
#3: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 533 / Source method: isolated from a natural source / Formula: H2O

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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
Details: 0.1 M Bis-Tris pH 6.0 or Hepes pH 7.5, 0.2 M ammonium acetate, 28% to 32% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.66→50 Å / Num. obs: 65103 / % possible obs: 95.9 % / Redundancy: 3.2 % / Rmerge(I) obs: 0.061 / Net I/σ(I): 10.5
Reflection shellResolution: 1.66→1.69 Å / Rmerge(I) obs: 0.474 / Num. measured obs: 3238

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Processing

Software
NameVersionClassification
PHENIX(dev_3139: ???)refinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6D9X

6d9x


Resolution: 1.66→36.415 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.97 / Phase error: 24.58
RfactorNum. reflection% reflection
Rfree0.2095 1999 3.07 %
Rwork0.1817 --
obs0.1826 65060 95.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.66→36.415 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4668 0 83 537 5288
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064923
X-RAY DIFFRACTIONf_angle_d0.8286688
X-RAY DIFFRACTIONf_dihedral_angle_d13.2312927
X-RAY DIFFRACTIONf_chiral_restr0.059737
X-RAY DIFFRACTIONf_plane_restr0.006828
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6564-1.69780.30131300.27264083X-RAY DIFFRACTION86
1.6978-1.74370.25551430.24324520X-RAY DIFFRACTION95
1.7437-1.7950.26481440.22814555X-RAY DIFFRACTION96
1.795-1.8530.26541420.21214483X-RAY DIFFRACTION96
1.853-1.91920.24841450.19814565X-RAY DIFFRACTION96
1.9192-1.9960.24381430.18584519X-RAY DIFFRACTION96
1.996-2.08690.23281450.18694590X-RAY DIFFRACTION97
2.0869-2.19690.19881460.18444578X-RAY DIFFRACTION97
2.1969-2.33450.24021450.18574584X-RAY DIFFRACTION97
2.3345-2.51470.21431450.19024595X-RAY DIFFRACTION97
2.5147-2.76770.23021460.19234588X-RAY DIFFRACTION97
2.7677-3.1680.19571450.18024550X-RAY DIFFRACTION96
3.168-3.99050.18121400.15974433X-RAY DIFFRACTION94
3.9905-36.42420.17691400.16124418X-RAY DIFFRACTION93
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)
11.584-0.7788-0.56641.03220.47081.3035-0.0354-0.00130.0353-0.10680.0395-0.0603-0.07140.0796-0.00390.1565-0.02390.00060.1924-0.01840.14867.63836.9989-6.1592
21.6217-0.1821-0.58681.485-0.08121.6987-0.0894-0.0042-0.0144-0.02680.06460.1565-0.0485-0.16990.04420.12760.0023-0.01990.2083-0.02220.181-10.30567.5741.1769
32.877-0.79510.43851.4465-0.40491.7083-0.1398-0.0079-0.43350.02870.04730.25290.3871-0.34060.12340.2146-0.04580.04260.2738-0.03930.2699-12.3266-4.26522.5992
41.60720.0038-0.78151.236-0.30631.6707-0.2186-0.1564-0.36670.10710.10290.12090.38020.06930.0860.25260.02460.0680.16250.03430.23143.7455-10.31952.3265
50.89640.047-0.23830.853-0.1131.2478-0.0544-0.12840.02930.14560.037-0.2754-0.08560.47390.05130.1419-0.0145-0.04910.3455-0.03460.210635.051918.8134.4094
61.2082-0.236-0.39511.02130.16131.8783-0.10860.0642-0.16980.0486-0.06040.04430.3259-0.0670.14390.1707-0.00740.02320.199-0.03360.199719.64048.153630.0641
70.37270.1679-0.13480.6397-0.65032.25470.01470.10010.0529-0.0392-0.04210.232-0.3357-0.56720.08030.15410.0462-0.01460.2987-0.0520.176710.739222.675823.5857
81.1498-0.0139-0.15881.7437-0.29552.49040.12060.00210.2133-0.02860.0158-0.0968-0.64290.2223-0.10330.2448-0.06670.00270.2042-0.02110.191526.775331.507526.1287
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 32 through 125 )
2X-RAY DIFFRACTION2chain 'A' and (resid 126 through 199 )
3X-RAY DIFFRACTION3chain 'A' and (resid 200 through 233 )
4X-RAY DIFFRACTION4chain 'A' and (resid 234 through 334 )
5X-RAY DIFFRACTION5chain 'B' and (resid 32 through 84 )
6X-RAY DIFFRACTION6chain 'B' and (resid 85 through 167 )
7X-RAY DIFFRACTION7chain 'B' and (resid 168 through 233 )
8X-RAY DIFFRACTION8chain 'B' and (resid 234 through 334 )

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