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- PDB-8g3e: Crystal structure of human WDR5 in complex with (1M)-N-[(3,5-difl... -

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Basic information

Entry
Database: PDB / ID: 8g3e
TitleCrystal structure of human WDR5 in complex with (1M)-N-[(3,5-difluoro[1,1'-biphenyl]-4-yl)methyl]-6-methyl-4-oxo-1-(pyridin-3-yl)-1,4-dihydropyridazine-3-carboxamide (compound 2, WDR5-MYC inhibitor)
ComponentsWD repeat-containing protein 5
KeywordsONCOPROTEIN/INHIBITOR / WDR5 / MYC / WBM / small molecule / ONCOPROTEIN-INHIBITOR complex
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. / 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
Similarity search - Domain/homology
Chem-YJR / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.33 Å
AuthorsZhao, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)-MYC Interaction.
Authors: Ding, J. / Liu, L. / Chiang, Y.L. / Zhao, M. / Liu, H. / Yang, F. / Shen, L. / Lin, Y. / Deng, H. / Gao, J. / Sage, D.R. / West, L. / Llamas, L.A. / Hao, X. / Kawatkar, S. / Li, E. / Jain, R. ...Authors: Ding, J. / Liu, L. / Chiang, Y.L. / Zhao, M. / Liu, H. / Yang, F. / Shen, L. / Lin, Y. / Deng, H. / Gao, J. / Sage, D.R. / West, L. / Llamas, L.A. / Hao, X. / Kawatkar, S. / Li, E. / Jain, R.K. / Tallarico, J.A. / Canham, S.M. / Wang, H.
History
DepositionFeb 7, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _pdbx_initial_refinement_model.details

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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)70,1914
Polymers69,3272
Non-polymers8652
Water11,169620
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0962
Polymers34,6631
Non-polymers4321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0962
Polymers34,6631
Non-polymers4321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.662, 62.276, 64.381
Angle α, β, γ (deg.)114.09, 91.08, 110.17
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: 34663.250 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-YJR / (1M)-N-[(3,5-difluoro[1,1'-biphenyl]-4-yl)methyl]-6-methyl-4-oxo-1-(pyridin-3-yl)-1,4-dihydropyridazine-3-carboxamide


Mass: 432.422 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H18F2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 620 / 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: 2.27 Å3/Da / Density % sol: 45.86 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 23.5% PEG3350, 0.21 M ammonium sulfate, 0.1 M HEPES, pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 30, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.33→32.35 Å / Num. obs: 133465 / % possible obs: 88.9 % / Redundancy: 2.3 % / Rmerge(I) obs: 0.063 / Net I/σ(I): 7.15
Reflection shellResolution: 1.33→1.363 Å / Rmerge(I) obs: 1 / Num. unique obs: 8976

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Processing

Software
NameVersionClassification
REFMACv5.8.0253refinement
XSCALEdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 8F1G

8f1g


Resolution: 1.33→32.35 Å / Cor.coef. Fo:Fc: 0.982 / Cor.coef. Fo:Fc free: 0.976 / SU B: 2.318 / SU ML: 0.04 / Cross valid method: THROUGHOUT / ESU R: 0.051 / ESU R Free: 0.049 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17047 6674 5 %RANDOM
Rwork0.13908 ---
obs0.14066 126790 94.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.439 Å2
Baniso -1Baniso -2Baniso -3
1--0.09 Å20.26 Å2-0.14 Å2
2--0.59 Å20.1 Å2
3----0.59 Å2
Refinement stepCycle: 1 / Resolution: 1.33→32.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4765 0 64 620 5449
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0134983
X-RAY DIFFRACTIONr_bond_other_d0.0180.0174515
X-RAY DIFFRACTIONr_angle_refined_deg1.3231.6456770
X-RAY DIFFRACTIONr_angle_other_deg1.6441.58310558
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.3685625
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.89924.845194
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.18815849
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.726156
X-RAY DIFFRACTIONr_chiral_restr0.0660.2662
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025508
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02964
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3491.8732476
X-RAY DIFFRACTIONr_mcbond_other1.3491.8732475
X-RAY DIFFRACTIONr_mcangle_it1.6842.8113088
X-RAY DIFFRACTIONr_mcangle_other1.6852.8123089
X-RAY DIFFRACTIONr_scbond_it1.7272.2172507
X-RAY DIFFRACTIONr_scbond_other1.6532.1692436
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.0763.133577
X-RAY DIFFRACTIONr_long_range_B_refined3.11324.0855674
X-RAY DIFFRACTIONr_long_range_B_other2.73323.1175443
X-RAY DIFFRACTIONr_rigid_bond_restr4.29139498
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.33→1.363 Å
RfactorNum. reflection% reflection
Rfree0.389 473 -
Rwork0.352 8976 -
obs--90.95 %

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