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- PDB-9b9h: Crystal structure of the ternary complex of DCAF1 and WDR5 with P... -

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Basic information

Entry
Database: PDB / ID: 9b9h
TitleCrystal structure of the ternary complex of DCAF1 and WDR5 with PROTAC, OICR-40333
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 / 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 / Cul4-RING E3 ubiquitin ligase complex / NSL complex / histone H3K4 methyltransferase activity ...cell competition in a multicellular organism / 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 / Cul4-RING E3 ubiquitin ligase 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 / ubiquitin-like ligase-substrate adaptor activity / : / positive regulation of gluconeogenesis / post-translational protein modification / B cell differentiation / transcription initiation-coupled chromatin remodeling / gluconeogenesis / skeletal system development / nuclear estrogen receptor binding / 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 / HATs acetylate histones / Neddylation / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / histone binding / proteasome-mediated ubiquitin-dependent protein catabolic process / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / 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 / 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. / WD domain, G-beta repeat ...VPRBP/DCAF1 family / Lissencephaly type-1-like homology motif / 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. / 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
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: 2.06 Å
AuthorsMabanglo, M.F. / Wilson, B.J. / Alvarez, H.G. / 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 2, 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
B: DDB1- and CUL4-associated factor 1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,9873
Polymers74,7322
Non-polymers1,2551
Water5,585310
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84.213, 85.143, 111.644
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 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
#2: 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(DE3) (bacteria) / References: UniProt: P61964
#3: Chemical ChemComp-A1AM2 / N-{(1P)-5'-({(17E)-18-[(3P)-4-{[(1S)-3-amino-1-(3-chloro-4-fluorophenyl)-3-oxopropyl]carbamoyl}-3-(4-chloro-2-fluorophenyl)-1H-pyrrol-2-yl]-16-oxo-3,6,9,12-tetraoxa-15-azaoctadec-17-en-1-yl}carbamoyl)-2'-fluoro-4-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl][1,1'-biphenyl]-3-yl}-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide / OICR-40333


Mass: 1255.093 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C60H63Cl2F6N9O10 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 310 / 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: 2.89 Å3/Da / Density % sol: 57.49 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 5% w/v 1-ethyl-3-methylimidazolium ethyl sulfate, 15% w/v polyethylene glycol 20,000, pH 7.9

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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 S 6M / Detector: PIXEL / Date: Feb 14, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1808 Å / Relative weight: 1
ReflectionResolution: 2.06→42.57 Å / Num. obs: 49405 / % possible obs: 95.17 % / Redundancy: 2 % / Biso Wilson estimate: 37.78 Å2 / CC1/2: 1 / CC star: 1 / Rmerge(I) obs: 0.01625 / Rpim(I) all: 0.01625 / Rrim(I) all: 0.02298 / Net I/σ(I): 25.11
Reflection shellResolution: 2.06→2.1 Å / Rmerge(I) obs: 0.6408 / Mean I/σ(I) obs: 1.05 / Num. unique obs: 2399 / CC1/2: 0.952 / Rpim(I) all: 0.6408 / Rrim(I) all: 0.9062

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XDSdata reduction
pointlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.06→42.57 Å / SU ML: 0.2828 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 27.7492
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2291 2395 5 %
Rwork0.2108 45496 -
obs0.2117 47891 95.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.56 Å2
Refinement stepCycle: LAST / Resolution: 2.06→42.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4946 0 0 310 5256
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.65765033
X-RAY DIFFRACTIONf_angle_d1.83646820
X-RAY DIFFRACTIONf_chiral_restr0.0523760
X-RAY DIFFRACTIONf_plane_restr0.0389871
X-RAY DIFFRACTIONf_dihedral_angle_d13.97451794
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.06-2.10.58261060.52751885X-RAY DIFFRACTION68.18
2.1-2.150.29331520.30192662X-RAY DIFFRACTION96.5
2.15-2.20.33071600.26772694X-RAY DIFFRACTION98.28
2.2-2.250.38641030.39782096X-RAY DIFFRACTION75.31
2.25-2.310.34151360.29572390X-RAY DIFFRACTION86.48
2.31-2.380.29061330.23612810X-RAY DIFFRACTION100
2.38-2.460.25531540.23632762X-RAY DIFFRACTION100
2.46-2.550.29521110.24652828X-RAY DIFFRACTION100
2.55-2.650.27771360.25412747X-RAY DIFFRACTION97.66
2.65-2.770.28461270.25262730X-RAY DIFFRACTION97.74
2.77-2.910.2621760.22962786X-RAY DIFFRACTION99.93
2.91-3.10.23381430.23762802X-RAY DIFFRACTION100
3.1-3.340.231620.21412806X-RAY DIFFRACTION99.9
3.34-3.670.19961490.20072793X-RAY DIFFRACTION98.53
3.67-4.20.19691510.17222804X-RAY DIFFRACTION98.99
4.2-5.290.15831310.14512905X-RAY DIFFRACTION99.97
5.29-42.570.18481650.19092996X-RAY DIFFRACTION99.68

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