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- PDB-9b9w: Crystal structure of the ternary complex of DCAF1 and WDR5 with P... -

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Basic information

Entry
Database: PDB / ID: 9b9w
TitleCrystal structure of the ternary complex of DCAF1 and WDR5 with PROTAC, OICR-40792
Components
  • DDB1- and CUL4-associated factor 1
  • WD repeat-containing protein 5
KeywordsPROTEIN BINDING / E3 ligase / adaptor / PROTAC / WDR / ternary complex
Function / homology
Function and homology information


cell competition in a multicellular organism / histone H2AT120 kinase activity / histone H3Q5ser reader activity / histone H3K4me1 reader activity / V(D)J recombination / Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex ...cell competition in a multicellular organism / histone H2AT120 kinase activity / histone H3Q5ser reader activity / histone H3K4me1 reader activity / V(D)J recombination / 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 / Cul4-RING E3 ubiquitin ligase complex / Formation of WDR5-containing histone-modifying complexes / histone methyltransferase complex / regulation of cell division / MLL1 complex / regulation of embryonic development / histone acetyltransferase complex / ubiquitin-like ligase-substrate adaptor activity / positive regulation of gluconeogenesis / post-translational protein modification / transcription initiation-coupled chromatin remodeling / B cell differentiation / nuclear estrogen receptor binding / 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 / fibrillar center / positive regulation of protein catabolic process / mitotic spindle / Antigen processing: Ubiquitination & Proteasome degradation / Neddylation / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / histone binding / proteasome-mediated ubiquitin-dependent protein catabolic process / non-specific serine/threonine protein kinase / regulation of cell cycle / protein ubiquitination / protein serine kinase activity / centrosome / 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 / ATP binding / nucleus / cytoplasm
Similarity search - Function
VPRBP/DCAF1 family / Lissencephaly type-1-like homology motif / WDR5 beta-propeller domain / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Armadillo-like helical / Armadillo-type fold / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. ...VPRBP/DCAF1 family / Lissencephaly type-1-like homology motif / WDR5 beta-propeller domain / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Armadillo-like helical / Armadillo-type fold / 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
Similarity search - Domain/homology
: / WD repeat-containing protein 5 / DDB1- and CUL4-associated factor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsMabanglo, M.F. / Wilson, B.J. / Mamai, A. / Hoffer, L. / Al-awar, R. / Vedadi, M.
Funding support Canada, 1items
OrganizationGrant numberCountry
Ontario Institute for Cancer Research Canada
CitationJournal: Nat Commun / Year: 2024
Title: Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity.
Authors: Mabanglo, M.F. / Wilson, B. / Noureldin, M. / Kimani, S.W. / Mamai, A. / Krausser, C. / Gonzalez-Alvarez, H. / Srivastava, S. / Mohammed, M. / Hoffer, L. / Chan, M. / Avrumutsoae, J. / Li, A. ...Authors: Mabanglo, M.F. / Wilson, B. / Noureldin, M. / Kimani, S.W. / Mamai, A. / Krausser, C. / Gonzalez-Alvarez, H. / Srivastava, S. / Mohammed, M. / Hoffer, L. / Chan, M. / Avrumutsoae, J. / Li, A.S.M. / Hajian, T. / Tucker, S. / Green, S. / Szewczyk, M. / Barsyte-Lovejoy, D. / Santhakumar, V. / Ackloo, S. / Loppnau, P. / Li, Y. / Seitova, A. / Kiyota, T. / Wang, J.G. / Prive, G.G. / Kuntz, D.A. / Patel, B. / Rathod, V. / Vala, A. / Rout, B. / Aman, A. / Poda, G. / Uehling, D. / Ramnauth, J. / Halabelian, L. / Marcellus, R. / Al-Awar, R. / Vedadi, M.
History
DepositionApr 3, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2024Group: 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

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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: DDB1- and CUL4-associated factor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,0763
Polymers74,7322
Non-polymers1,3441
Water8,557475
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)79.895, 83.533, 130.828
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 36433.207 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 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P61964
#2: Protein DDB1- and CUL4-associated factor 1 / HIV-1 Vpr-binding protein / VprBP / Serine/threonine-protein kinase VPRBP / Vpr-interacting protein


Mass: 38298.820 Da / Num. of mol.: 1 / Fragment: residues 1080-1390
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DCAF1, KIAA0800, RIP, VPRBP / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9Y4B6, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-A1ANN / (4P)-N-[(1R)-3-amino-1-(3-chloro-4-fluorophenyl)-3-oxopropyl]-4-(4-chloro-2-fluorophenyl)-5-[(25E)-1-{(1P)-6-fluoro-3'-[4-fluoro-2-(trifluoromethyl)benzamido]-4'-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl][1,1'-biphenyl]-3-yl}-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazahexacos-25-en-26-yl]-1H-pyrrole-3-carboxamide / OICR-40792


Mass: 1344.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C65H71Cl2F7N8O11 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 475 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.92 Å3/Da / Density % sol: 57.9 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / Details: 35% v/v tacsimate, pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08B1-1 / Wavelength: 1.1808 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 1, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1808 Å / Relative weight: 1
ReflectionResolution: 1.92→43.29 Å / Num. obs: 67507 / % possible obs: 99.98 % / Redundancy: 2 % / Biso Wilson estimate: 28.11 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.03192 / Rpim(I) all: 0.03192 / Rrim(I) all: 0.04515 / Net I/σ(I): 15.04 / Num. measured all: 134923
Reflection shellResolution: 1.92→1.95 Å / Num. measured all: 5506 / Num. unique obs: 2761 / CC1/2: 0.594 / CC star: 0.863

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XDSdata reduction
pointlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.92→43.29 Å / SU ML: 0.1778 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 17.4417
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.183 3397 5.03 %
Rwork0.1719 64103 -
obs0.1725 67500 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 31.07 Å2
Refinement stepCycle: LAST / Resolution: 1.92→43.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4747 0 93 475 5315
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00664904
X-RAY DIFFRACTIONf_angle_d0.85296663
X-RAY DIFFRACTIONf_chiral_restr0.0581748
X-RAY DIFFRACTIONf_plane_restr0.0075847
X-RAY DIFFRACTIONf_dihedral_angle_d12.98011752
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
1.92-1.950.25931390.264626222761100
1.95-1.980.28691350.2623260499.96
1.98-2.010.26021580.24182663100
2.01-2.040.2471150.22092671100
2.04-2.080.25941410.22452614100
2.08-2.110.26381440.21582611100
2.11-2.150.22171380.202267699.96
2.15-2.20.20781520.1964261399.96
2.2-2.250.18231400.19962650100
2.25-2.30.19661410.19652656100
2.3-2.360.21141330.1912679100
2.36-2.420.2251310.19342648100
2.42-2.490.22071430.19512633100
2.49-2.570.21961430.1906268699.96
2.57-2.660.18451420.1887263799.96
2.66-2.770.2021490.1811267699.96
2.77-2.890.17681340.18232678100
2.9-3.050.18761350.19082673100
3.05-3.240.19431390.16872689100
3.24-3.490.15811280.1483271999.93
3.49-3.840.14581320.14612696100
3.84-4.390.14581670.1304270299.93
4.39-5.530.13921580.1322273899.97
5.54-43.290.1791600.1692286999.87

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