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- PDB-6e1y: Discovery of Potent 2-Aryl-6,7-Dihydro-5HPyrrolo[ 1,2-a]imidazole... -

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Basic information

Entry
Database: PDB / ID: 6e1y
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
Keywordsgene regulation/inhibitor / WDR5 / WIN-site / fragment screening / structure-based design / mixed-lineage leukemia / DNA BINDING PROTEIN / dna binding protein-inhibitor complex / GENE REGULATION / gene regulation-inhibitor complex
Function / homology
Function and homology information


histone H3Q5ser reader activity / histone H3K4me1 reader activity / 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 ...histone H3Q5ser reader activity / histone H3K4me1 reader activity / 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 / Formation of WDR5-containing histone-modifying complexes / histone methyltransferase complex / regulation of cell division / MLL1 complex / regulation of embryonic development / histone acetyltransferase complex / positive regulation of gluconeogenesis / transcription initiation-coupled chromatin remodeling / 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 / mitotic spindle / HATs acetylate histones / Neddylation / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / 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
WDR5 beta-propeller domain / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats ...WDR5 beta-propeller domain / 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. / 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 / Mainly Beta
Similarity search - Domain/homology
Chem-HLM / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.219 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: Cell Rep / Year: 2019
Title: Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.
Authors: Aho, E.R. / Wang, J. / Gogliotti, R.D. / Howard, G.C. / Phan, J. / Acharya, P. / Macdonald, J.D. / Cheng, K. / Lorey, S.L. / Lu, B. / Wenzel, S. / Foshage, A.M. / Alvarado, J. / Wang, F. / ...Authors: Aho, E.R. / Wang, J. / Gogliotti, R.D. / Howard, G.C. / Phan, J. / Acharya, P. / Macdonald, J.D. / Cheng, K. / Lorey, S.L. / Lu, B. / Wenzel, S. / Foshage, A.M. / Alvarado, J. / Wang, F. / Shaw, J.G. / Zhao, B. / Weissmiller, A.M. / Thomas, L.R. / Vakoc, C.R. / Hall, M.D. / Hiebert, S.W. / Liu, Q. / Stauffer, S.R. / Fesik, S.W. / Tansey, W.P.
History
DepositionJul 10, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2019Group: Data collection / 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
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 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

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)69,4964
Polymers68,7822
Non-polymers7142
Water15,727873
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7482
Polymers34,3911
Non-polymers3571
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7482
Polymers34,3911
Non-polymers3571
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.971, 61.573, 64.668
Angle α, β, γ (deg.)110.47, 91.22, 112.27
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: 34390.992 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-HLM / N-[(1S)-1-(3-chlorophenyl)ethyl]-3-{[(4,5-dihydro-1H-imidazol-2-yl)amino]methyl}benzamide


Mass: 356.849 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H21ClN4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 873 / 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: 2.36 Å3/Da / Density % sol: 47.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M Bis-Tris pH 6.0 or Hepes pH 7.5, 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-F / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.219→50 Å / Num. obs: 173496 / % possible obs: 94.1 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 14.68
Reflection shellResolution: 1.22→1.24 Å / Rmerge(I) obs: 0.292

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Processing

Software
NameVersionClassification
PHENIX(dev_3139: ???)refinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6D9X

6d9x


Resolution: 1.219→29.016 Å / SU ML: 0.11 / Cross valid method: FREE R-VALUE / σ(F): 1.97 / Phase error: 21.65
RfactorNum. reflection% reflection
Rfree0.1816 1983 1.14 %
Rwork0.1697 --
obs0.1699 173380 93.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.219→29.016 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4702 0 0 882 5584
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084951
X-RAY DIFFRACTIONf_angle_d1.1136733
X-RAY DIFFRACTIONf_dihedral_angle_d18.1081761
X-RAY DIFFRACTIONf_chiral_restr0.093750
X-RAY DIFFRACTIONf_plane_restr0.007849
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2189-1.24940.32511300.274710948X-RAY DIFFRACTION84
1.2494-1.28320.26391350.252511663X-RAY DIFFRACTION89
1.2832-1.32090.22541390.236211987X-RAY DIFFRACTION92
1.3209-1.36360.25191470.223612102X-RAY DIFFRACTION93
1.3636-1.41230.21881320.212112177X-RAY DIFFRACTION93
1.4123-1.46890.22581390.201312253X-RAY DIFFRACTION94
1.4689-1.53570.21921350.192612277X-RAY DIFFRACTION95
1.5357-1.61670.20341390.176912404X-RAY DIFFRACTION95
1.6167-1.71790.17161480.17112375X-RAY DIFFRACTION95
1.7179-1.85060.18591440.168812525X-RAY DIFFRACTION96
1.8506-2.03680.15431530.159412545X-RAY DIFFRACTION96
2.0368-2.33140.1661370.154812690X-RAY DIFFRACTION97
2.3314-2.93680.18171570.15412777X-RAY DIFFRACTION98
2.9368-29.02470.15221480.148712674X-RAY DIFFRACTION97

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