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Basic information

Entry
Database: PDB / ID: 6ucs
TitleDiscovery and Structure-Based optimization of potent and selective WDR5 inhibitors containing a dihydroisoquinolinone bicyclic core
ComponentsWD repeat-containing protein 5
KeywordsTRANSCRIPTION / WDR5 / structure-based design / mixed-lineage leukemia
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 / Neddylation / HATs acetylate histones / 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 / WD domain, G-beta repeat / 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. ...WDR5 beta-propeller domain / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / WD domain, G-beta repeat / 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-Q41 / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsZhao, B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
Authors: Tian, J. / Teuscher, K.B. / Aho, E.R. / Alvarado, J.R. / Mills, J.J. / Meyers, K.M. / Gogliotti, R.D. / Han, C. / Macdonald, J.D. / Sai, J. / Shaw, J.G. / Sensintaffar, J.L. / Zhao, B. / ...Authors: Tian, J. / Teuscher, K.B. / Aho, E.R. / Alvarado, J.R. / Mills, J.J. / Meyers, K.M. / Gogliotti, R.D. / Han, C. / Macdonald, J.D. / Sai, J. / Shaw, J.G. / Sensintaffar, J.L. / Zhao, B. / Rietz, T.A. / Thomas, L.R. / Payne, W.G. / Moore, W.J. / Stott, G.M. / Kondo, J. / Inoue, M. / Coffey, R.J. / Tansey, W.P. / Stauffer, S.R. / Lee, T. / Fesik, S.W.
History
DepositionSep 17, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation.year ..._citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Feb 5, 2020Group: 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 1.3Oct 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 2.0May 15, 2024Group: Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / entity / pdbx_entity_nonpoly
Item: _chem_comp.formula / _chem_comp.name ..._chem_comp.formula / _chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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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)69,8134
Polymers68,7822
Non-polymers1,0312
Water8,449469
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9072
Polymers34,3911
Non-polymers5161
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)34,9072
Polymers34,3911
Non-polymers5161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.566, 47.099, 68.984
Angle α, β, γ (deg.)89.060, 89.820, 74.180
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and ((resid 31 and (name N or name...
21(chain B and ((resid 31 and (name N or name...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11VALVALVALVAL(chain A and ((resid 31 and (name N or name...AA3110
12ALAALACYSCYS(chain A and ((resid 31 and (name N or name...AA23 - 3342 - 313
13ALAALACYSCYS(chain A and ((resid 31 and (name N or name...AA23 - 3342 - 313
14ALAALACYSCYS(chain A and ((resid 31 and (name N or name...AA23 - 3342 - 313
15ALAALACYSCYS(chain A and ((resid 31 and (name N or name...AA23 - 3342 - 313
21VALVALVALVAL(chain B and ((resid 31 and (name N or name...BB3110
22THRTHRCYSCYS(chain B and ((resid 31 and (name N or name...BB24 - 3343 - 313
23THRTHRCYSCYS(chain B and ((resid 31 and (name N or name...BB24 - 3343 - 313
24THRTHRCYSCYS(chain B and ((resid 31 and (name N or name...BB24 - 3343 - 313
25THRTHRCYSCYS(chain B and ((resid 31 and (name N or name...BB24 - 3343 - 313

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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 K-12 (bacteria) / References: UniProt: P61964
#2: Chemical ChemComp-Q41 / 2-amino-3-{[(5P)-2-[(3,5-dimethoxyphenyl)methyl]-5-(4-fluoro-2-methylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]methyl}-1-methyl-1H-imidazol-3-ium


Mass: 515.598 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H32FN4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 469 / 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: 2.15 Å3/Da / Density % sol: 42.66 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: Bis-Tris, Ammonium Acetate, PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.987 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jan 30, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.85→40 Å / Num. obs: 44095 / % possible obs: 91.8 % / Redundancy: 2.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.049 / Rrim(I) all: 0.082 / Rsym value: 0.066 / Net I/σ(I): 15.6
Reflection shellResolution: 1.85→1.88 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.352 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 2031 / CC1/2: 0.753 / Rpim(I) all: 0.207 / Rrim(I) all: 0.329 / Rsym value: 0.253 / % possible all: 83

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DY7

6dy7


Resolution: 1.85→28.24 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 2.01 / Phase error: 18.77 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1942 2013 4.57 %
Rwork0.1665 42057 -
obs0.1678 44070 91.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 64.31 Å2 / Biso mean: 22.1006 Å2 / Biso min: 9 Å2
Refinement stepCycle: final / Resolution: 1.85→28.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4650 0 76 469 5195
Biso mean--18.4 32.59 -
Num. residues----614
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0054942
X-RAY DIFFRACTIONf_angle_d1.0016735
X-RAY DIFFRACTIONf_chiral_restr0.112756
X-RAY DIFFRACTIONf_plane_restr0.006837
X-RAY DIFFRACTIONf_dihedral_angle_d7.5653896
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2644X-RAY DIFFRACTION5.481TORSIONAL
12B2644X-RAY DIFFRACTION5.481TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.8503-1.89650.23191200.2181264681
1.8965-1.94780.23371440.201289788
1.9478-2.00510.24821390.194282388
2.0051-2.06980.26151400.1796293989
2.0698-2.14370.19631420.1698297390
2.1437-2.22950.20511390.1703299391
2.2295-2.3310.22041440.176297491
2.331-2.45380.18641360.1747306693
2.4538-2.60740.19781420.1752306894
2.6074-2.80860.22511510.1696306494
2.8086-3.09090.20281580.1698310494
3.0909-3.53740.17041540.1492311496
3.5374-4.4540.16321580.1409317697
4.454-28.240.16791460.1651322098
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)
11.0166-0.1657-0.16190.61950.03920.91660.0110.0731-0.1092-0.07510.00110.02260.0364-0.0301-0.01640.1114-0.0441-0.00230.1165-0.01470.1229-15.20124.002-1.4552
22.362-0.9807-0.80841.4623-0.17351.93150.09830.04340.1887-0.0733-0.0625-0.283-0.210.1644-0.04810.1284-0.04680.0020.1841-0.0010.1729-0.30335.04530.3408
31.80760.2613-0.33661.8783-0.09131.94130.06430.08920.2117-0.046-0.0566-0.113-0.14120.0009-0.01890.14660.01550.00040.12260.02390.157-16.30941.9839-6.2532
41.30550.2036-0.35780.6169-0.1771.2414-0.0305-0.0880.15780.08330.0638-0.004-0.1298-0.0804-0.040.16830.0281-0.02360.1602-0.01720.13668.829138.1142-37.4965
52.86531.3243-0.21781.9459-0.45771.619-0.0189-0.4141-0.23520.1297-0.0846-0.270.15440.19760.09610.15210.0569-0.01320.23550.00850.161923.118126.1295-36.3495
61.5905-0.1934-0.52861.9986-0.32492.2819-0.0748-0.021-0.1335-0.00660.0329-0.06690.17-0.01410.04960.1528-0.01510.00320.14190.00210.13226.53519.8591-31.2473
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 24 through 167 )A24 - 167
2X-RAY DIFFRACTION2chain 'A' and (resid 168 through 233 )A168 - 233
3X-RAY DIFFRACTION3chain 'A' and (resid 234 through 334 )A234 - 334
4X-RAY DIFFRACTION4chain 'B' and (resid 31 through 179 )B31 - 179
5X-RAY DIFFRACTION5chain 'B' and (resid 180 through 233 )B180 - 233
6X-RAY DIFFRACTION6chain 'B' and (resid 234 through 334 )B234 - 334

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