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- PDB-7uas: Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5)... -

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Basic information

Entry
Database: PDB / ID: 7uas
TitleDiscovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization
ComponentsWD repeat-containing protein 5
KeywordsTranscription/Transcription Inhibitor / WDR5 / structure-based design / Transcription-Transcription 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 / Formation of WDR5-containing histone-modifying complexes / regulation of cell division / regulation of embryonic development / MLL1 complex / 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. / 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
Similarity search - Domain/homology
Chem-MBU / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.808 Å
AuthorsZhao, B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA68485 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization.
Authors: Teuscher, K.B. / Meyers, K.M. / Wei, Q. / Mills, J.J. / Tian, J. / Alvarado, J. / Sai, J. / Van Meveren, M. / South, T.M. / Rietz, T.A. / Zhao, B. / Moore, W.J. / Stott, G.M. / Tansey, W.P. ...Authors: Teuscher, K.B. / Meyers, K.M. / Wei, Q. / Mills, J.J. / Tian, J. / Alvarado, J. / Sai, J. / Van Meveren, M. / South, T.M. / Rietz, T.A. / Zhao, B. / Moore, W.J. / Stott, G.M. / Tansey, W.P. / Lee, T. / Fesik, S.W.
History
DepositionMar 14, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: 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 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)69,8794
Polymers68,7822
Non-polymers1,0972
Water11,782654
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9402
Polymers34,3911
Non-polymers5491
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9402
Polymers34,3911
Non-polymers5491
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.743, 53.857, 64.519
Angle α, β, γ (deg.)107.960, 91.310, 109.390
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-MBU / (5P)-2-[(S)-cyclopropyl(4-methylpyridin-2-yl)methyl]-5-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-[(2-methyl-1H-imidazol-1-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one


Mass: 548.602 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H31F3N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 654 / 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: 2.1 Å3/Da / Density % sol: 41.38 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: Bis-Tris, Ammonium Acetate, PEG 3350 / PH range: 5.5-7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Mar 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 49764 / % possible obs: 96.6 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.3 % / Biso Wilson estimate: 14.03 Å2 / CC1/2: 0.991 / CC star: 0.998 / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.042 / Rrim(I) all: 0.077 / Rsym value: 0.065 / Χ2: 1.41 / Net I/av σ(I): 22.6 / Net I/σ(I): 26
Reflection shellResolution: 1.8→1.83 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.236 / Mean I/σ(I) obs: 3.9 / Num. unique obs: 1983 / CC1/2: 0.893 / CC star: 0.971 / Rpim(I) all: 0.176 / Rrim(I) all: 0.309 / Rsym value: 0.252 / Χ2: 0.955 / % possible all: 77.2

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.13_2998refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6UCS

6ucs


Resolution: 1.808→28.429 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 16.61 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1749 1999 4.02 %
Rwork0.1372 47756 -
obs0.1387 49755 97.17 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 57.53 Å2 / Biso mean: 17.3149 Å2 / Biso min: 6.3 Å2
Refinement stepCycle: final / Resolution: 1.808→28.429 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4627 0 80 654 5361
Biso mean--13.09 28.19 -
Num. residues----606
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.808-1.85270.25761330.1763319190
1.8527-1.90280.19721430.1539339297
1.9028-1.95880.18341420.138340297
1.9588-2.0220.18371420.131340597
2.022-2.09420.17581410.1312337397
2.0942-2.17810.19431430.134341897
2.1781-2.27710.19211420.1397340197
2.2771-2.39710.19391430.146341397
2.3971-2.54720.18841440.1466345098
2.5472-2.74380.18711440.15343798
2.7438-3.01960.18771450.1438344098
3.0196-3.45590.1721460.1368348299
3.4559-4.35160.13611450.12346399
4.3516-28.40.14661460.1291348999
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)
11.14560.0320.05980.99940.10061.0338-0.0392-0.02230.06330.05220.05410.0052-0.02440.0065-0.01820.07410.0116-0.00250.0603-0.00070.0713-11.8975-20.3315-13.0602
22.81670.9363-0.67041.34760.57281.23470.02930.0939-0.28660.00580.1416-0.38860.33710.4093-0.0640.15770.0448-0.0340.1482-0.05480.194-2.9445-33.9267-19.5099
31.1939-0.1398-0.1051.47930.29731.43270.02950.0022-0.19210.05990.01950.01060.1922-0.0025-0.05030.1238-0.0109-0.01270.0843-0.00470.1294-16.7591-37.8492-16.6356
40.9011-0.10780.06011.1721-0.0640.95660.00490.0243-0.0118-0.1097-0.02170.09490.0079-0.03860.00460.09790.0029-0.00610.09660.0020.102-0.6102-32.489411.3688
50.98590.10120.08461.18590.12231.0630.0003-0.0054-0.0982-0.09410.0067-0.10330.03990.05350.00170.09180.01370.01980.08150.01060.102215.8406-38.621216.221
62.1627-0.393-0.13261.69360.2871.25790.023-0.08570.1010.0578-0.0239-0.268-0.15170.1808-0.02130.1255-0.0157-0.00130.1508-0.00630.145621.4531-25.210922.6024
71.21660.32830.42241.29070.51581.1551-0.023-0.0450.0752-0.0931-0.01280.0121-0.1445-0.0230.02920.12470.01410.00680.0888-0.00830.10514.8429-17.702419.3909
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 31 through 206 )A31 - 206
2X-RAY DIFFRACTION2chain 'A' and (resid 207 through 233 )A207 - 233
3X-RAY DIFFRACTION3chain 'A' and (resid 234 through 334 )A234 - 334
4X-RAY DIFFRACTION4chain 'B' and (resid 31 through 106 )B31 - 106
5X-RAY DIFFRACTION5chain 'B' and (resid 107 through 190 )B107 - 190
6X-RAY DIFFRACTION6chain 'B' and (resid 191 through 233 )B191 - 233
7X-RAY DIFFRACTION7chain 'B' and (resid 234 through 334 )B234 - 334

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