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- PDB-6d9x: Discovery of Potent 2-Aryl-6,7-Dihydro-5HPyrrolo[ 1,2-a]imidazole... -

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Basic information

Entry
Database: PDB / ID: 6d9x
TitleDiscovery of Potent 2-Aryl-6,7-Dihydro-5HPyrrolo[ 1,2-a]imidazoles as WDR5 WIN-site Inhibitors Using Fragment-Based Methods and Structure-Based Design
ComponentsWD repeat-containing protein 5
Keywordsdna binding protein/inhibitor / WDR5 / WIN-site / fragment screening / structure-based design / mixed-lineage leukemia / DNA BINDING PROTEIN / dna binding protein-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 ...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 / regulation of cell division / Formation of WDR5-containing histone-modifying complexes / MLL1 complex / regulation of embryonic development / 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
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 / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. ...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 / 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 / Mainly Beta
Similarity search - Domain/homology
2-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 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: J. Med. Chem. / Year: 2018
Title: Discovery of Potent 2-Aryl-6,7-dihydro-5 H-pyrrolo[1,2- a]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design.
Authors: Wang, F. / Jeon, K.O. / Salovich, J.M. / Macdonald, J.D. / Alvarado, J. / Gogliotti, R.D. / Phan, J. / Olejniczak, E.T. / Sun, Q. / Wang, S. / Camper, D. / Yuh, J.P. / Shaw, J.G. / Sai, J. / ...Authors: Wang, F. / Jeon, K.O. / Salovich, J.M. / Macdonald, J.D. / Alvarado, J. / Gogliotti, R.D. / Phan, J. / Olejniczak, E.T. / Sun, Q. / Wang, S. / Camper, D. / Yuh, J.P. / Shaw, J.G. / Sai, J. / Rossanese, O.W. / Tansey, W.P. / Stauffer, S.R. / Fesik, S.W.
History
DepositionApr 30, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 5, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 31, 2018Group: Data collection / Database references / Category: citation / Item: _citation.title
Revision 1.2Nov 7, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.3Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,5983
Polymers34,3911
Non-polymers2072
Water1,51384
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.291, 86.273, 40.288
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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.: 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-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-FZM / 2-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole


Mass: 184.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H12N2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 84 / 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 Å3/Da / Density % sol: 40 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.1 M Bis-Tris pH 6.0, 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-G / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 8, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.83→50 Å / Num. obs: 25685 / % possible obs: 99.1 % / Redundancy: 8 % / Rpim(I) all: 0.027 / Net I/σ(I): 19
Reflection shellResolution: 1.83→1.86 Å / Redundancy: 6.5 % / Num. unique obs: 1192 / Rpim(I) all: 0.264 / % possible all: 93.9

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Processing

Software
NameVersionClassification
PHENIXdev_1645refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Y7R

4y7r


Resolution: 1.83→29.443 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 36.15
RfactorNum. reflection% reflection
Rfree0.2413 1215 4.76 %
Rwork0.1981 --
obs0.2003 25547 98.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.83→29.443 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2364 0 15 84 2463
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072471
X-RAY DIFFRACTIONf_angle_d1.0233359
X-RAY DIFFRACTIONf_dihedral_angle_d12.168876
X-RAY DIFFRACTIONf_chiral_restr0.041376
X-RAY DIFFRACTIONf_plane_restr0.004417
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8256-1.89870.40941040.3272533X-RAY DIFFRACTION93
1.8987-1.98510.37891120.29652630X-RAY DIFFRACTION97
1.9851-2.08970.32631340.27692675X-RAY DIFFRACTION99
2.0897-2.22060.35031250.25272695X-RAY DIFFRACTION99
2.2206-2.3920.27131540.23732703X-RAY DIFFRACTION100
2.392-2.63260.27061410.25132697X-RAY DIFFRACTION100
2.6326-3.01320.26811320.23352752X-RAY DIFFRACTION100
3.0132-3.7950.25931290.18882789X-RAY DIFFRACTION100
3.795-29.44730.18021840.14082858X-RAY DIFFRACTION99

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