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

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Basic information

Entry
Database: PDB / ID: 6dar
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 / 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 / histone acetyltransferase complex / positive regulation of gluconeogenesis / methylated histone binding / transcription initiation-coupled chromatin remodeling / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats ...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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-G2J / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 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
DepositionMay 1, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,1416
Polymers34,3911
Non-polymers7505
Water8,161453
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)78.550, 99.466, 80.460
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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-G2J / N-(cyclopropylmethyl)-N-{[3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)phenyl]methyl}-3-methoxybenzamide


Mass: 401.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27N3O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 453 / 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: 2.28 Å3/Da / Density % sol: 46.17 %
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: 1.88→50 Å / Num. obs: 25974 / % possible obs: 99.8 % / Redundancy: 4.37 % / Rsym value: 0.089 / Net I/σ(I): 10.11
Reflection shellResolution: 1.88→1.92 Å / Redundancy: 2.77 % / Mean I/σ(I) obs: 2.07 / Num. unique obs: 1183 / Rsym value: 0.35 / % possible all: 98.3

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Processing

Software
NameVersionClassification
PHENIXdev_1760refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Y7R

4y7r


Resolution: 1.88→30.823 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.38
RfactorNum. reflection% reflection
Rfree0.1948 2561 9.96 %
Rwork0.1579 --
obs0.1615 25724 98.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.88→30.823 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2338 0 48 456 2842
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052533
X-RAY DIFFRACTIONf_angle_d1.0083454
X-RAY DIFFRACTIONf_dihedral_angle_d12.137912
X-RAY DIFFRACTIONf_chiral_restr0.039383
X-RAY DIFFRACTIONf_plane_restr0.004434
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.88-1.91620.32771240.22361206X-RAY DIFFRACTION93
1.9162-1.95530.2431320.19731212X-RAY DIFFRACTION96
1.9553-1.99780.25251450.20151251X-RAY DIFFRACTION98
1.9978-2.04420.23061280.18551310X-RAY DIFFRACTION99
2.0442-2.09540.25471310.19191264X-RAY DIFFRACTION100
2.0954-2.1520.20011530.16441262X-RAY DIFFRACTION100
2.152-2.21530.20761410.16641295X-RAY DIFFRACTION100
2.2153-2.28680.22831350.16991285X-RAY DIFFRACTION99
2.2868-2.36850.21631380.17421304X-RAY DIFFRACTION100
2.3685-2.46330.20911410.16171278X-RAY DIFFRACTION100
2.4633-2.57530.23561530.17011268X-RAY DIFFRACTION100
2.5753-2.7110.18921410.16771303X-RAY DIFFRACTION100
2.711-2.88080.19961380.15921309X-RAY DIFFRACTION100
2.8808-3.1030.19731540.1521283X-RAY DIFFRACTION100
3.103-3.41490.16061410.13791315X-RAY DIFFRACTION100
3.4149-3.90820.17091560.12781293X-RAY DIFFRACTION100
3.9082-4.92070.13091570.11881333X-RAY DIFFRACTION100
4.9207-30.82670.17671530.16411392X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.7189-0.0136-0.2560.3077-0.19430.86970.0081-0.0395-0.02340.01710.00250.01210.09230.00170.01020.1185-0.0106-0.00760.0911-0.00480.096228.433914.424111.7765
21.4772-0.29930.23570.6071-0.33520.87330.02590.2576-0.1033-0.0211-0.0129-0.04640.14390.0817-0.01070.12220.0081-0.00250.1374-0.01710.097127.886516.8665-7.9934
31.72340.15660.13410.5217-0.50850.5854-0.06570.3619-0.2297-0.18090.05560.05760.063-0.12350.00550.1383-0.00060.01190.1857-0.03530.136311.708217.35-6.1364
40.75510.02130.22520.2543-0.17491.1403-0.0093-0.0315-0.00560.01880.00760.0854-0.0454-0.1461-0.01380.07850.00870.00470.1052-0.00330.11111.027917.795310.9921
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 31 through 148 )
2X-RAY DIFFRACTION2chain 'A' and (resid 149 through 209 )
3X-RAY DIFFRACTION3chain 'A' and (resid 210 through 252 )
4X-RAY DIFFRACTION4chain 'A' and (resid 253 through 332 )

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