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- PDB-8e9f: WD repeat-containing protein 5 complexed with 4-(7-((1H-imidazol-... -

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Basic information

Entry
Database: PDB / ID: 8e9f
TitleWD repeat-containing protein 5 complexed with 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-N-methylquinoline-8-carboxamide (compound 10)
ComponentsWD repeat-containing protein 5
KeywordsTRANSCRIPTION / WDR5 / drug discovery / cancer
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 / transcription factor TFIID complex / RNA polymerase II general transcription initiation factor activity / histone acetyltransferase complex / positive regulation of gluconeogenesis / transcription initiation-coupled chromatin remodeling / methylated histone binding / 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
G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
BENZAMIDINE / Chem-UY9 / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsRietz, T.A. / Fesik, S.W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)HHSN261200800001E United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2023
Title: Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models.
Authors: Teuscher, K.B. / Chowdhury, S. / Meyers, K.M. / Tian, J. / Sai, J. / Van Meveren, M. / South, T.M. / Sensintaffar, J.L. / Rietz, T.A. / Goswami, S. / Wang, J. / Grieb, B.C. / Lorey, S.L. / ...Authors: Teuscher, K.B. / Chowdhury, S. / Meyers, K.M. / Tian, J. / Sai, J. / Van Meveren, M. / South, T.M. / Sensintaffar, J.L. / Rietz, T.A. / Goswami, S. / Wang, J. / Grieb, B.C. / Lorey, S.L. / Howard, G.C. / Liu, Q. / Moore, W.J. / Stott, G.M. / Tansey, W.P. / Lee, T. / Fesik, S.W.
History
DepositionAug 26, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2973
Polymers33,5891
Non-polymers7082
Water6,035335
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: fluorescence resonance energy transfer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.361, 86.040, 41.032
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

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


Mass: 33589.133 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 (E. coli) / References: UniProt: P61964
#2: Chemical ChemComp-BEN / BENZAMIDINE / Benzamidine


Mass: 120.152 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H8N2
#3: Chemical ChemComp-UY9 / 6-ethyl-4-[(5P)-7-[(1H-imidazol-1-yl)methyl]-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]-N-methylquinoline-8-carboxamide


Mass: 587.595 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H28F3N7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 335 / 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: 2.14 Å3/Da / Density % sol: 42.47 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: BIS-Tris, ammonium acetate, PEG 3350, benzamidine

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Feb 25, 2022
RadiationMonochromator: C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 1.55→29.56 Å / Num. obs: 42739 / % possible obs: 99.4 % / Redundancy: 7.9 % / Biso Wilson estimate: 17.31 Å2 / Rmerge(I) obs: 0.079 / Net I/σ(I): 38.3
Reflection shellResolution: 1.55→1.58 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.63 / Mean I/σ(I) obs: 3 / Num. unique obs: 2537 / % possible all: 95

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
DENZOdata reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3EG6

3eg6


Resolution: 1.55→29.56 Å / SU ML: 0.1559 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.1799
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1841 2057 4.84 %
Rwork0.1592 40461 -
obs0.1604 42518 99.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.01 Å2
Refinement stepCycle: LAST / Resolution: 1.55→29.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2364 0 52 335 2751
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00632487
X-RAY DIFFRACTIONf_angle_d0.88773384
X-RAY DIFFRACTIONf_chiral_restr0.0647374
X-RAY DIFFRACTIONf_plane_restr0.0065417
X-RAY DIFFRACTIONf_dihedral_angle_d11.7973334
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.55-1.580.27191280.24152548X-RAY DIFFRACTION95.06
1.58-1.620.28321600.21652616X-RAY DIFFRACTION99.07
1.62-1.670.20481530.19162623X-RAY DIFFRACTION99.39
1.67-1.720.22141260.18342707X-RAY DIFFRACTION99.26
1.72-1.770.22951310.17422638X-RAY DIFFRACTION99.5
1.77-1.840.21961500.1722654X-RAY DIFFRACTION99.75
1.84-1.910.21981380.16892682X-RAY DIFFRACTION99.82
1.91-20.22321180.16392706X-RAY DIFFRACTION99.82
2-2.10.19211210.1592702X-RAY DIFFRACTION100
2.1-2.230.1641300.15492707X-RAY DIFFRACTION99.89
2.23-2.40.19861350.16382748X-RAY DIFFRACTION99.93
2.4-2.650.17921230.1672716X-RAY DIFFRACTION99.93
2.65-3.030.19231330.16072747X-RAY DIFFRACTION99.97
3.03-3.820.14541530.14122783X-RAY DIFFRACTION100
3.82-29.560.16731580.14362884X-RAY DIFFRACTION99.48

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