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- PDB-6u80: Discovery and optimization of salicyclic acid-derived sulfonamide... -

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Basic information

Entry
Database: PDB / ID: 6u80
TitleDiscovery and optimization of salicyclic acid-derived sulfonamide inhibitors of the WDR5:MYC protein-protein interaction
ComponentsWD repeat-containing protein 5
KeywordsTRANSCRIPTION / WDR5 / MYC / RBBP5 / structure-based design / high-throughput screening
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-Q1J / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsZhao, B. / Wang, F.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction.
Authors: Macdonald, J.D. / Chacon Simon, S. / Han, C. / Wang, F. / Shaw, J.G. / Howes, J.E. / Sai, J. / Yuh, J.P. / Camper, D. / Alicie, B.M. / Alvarado, J. / Nikhar, S. / Payne, W. / Aho, E.R. / ...Authors: Macdonald, J.D. / Chacon Simon, S. / Han, C. / Wang, F. / Shaw, J.G. / Howes, J.E. / Sai, J. / Yuh, J.P. / Camper, D. / Alicie, B.M. / Alvarado, J. / Nikhar, S. / Payne, W. / Aho, E.R. / Bauer, J.A. / Zhao, B. / Phan, J. / Thomas, L.R. / Rossanese, O.W. / Tansey, W.P. / Waterson, A.G. / Stauffer, S.R. / Fesik, S.W.
History
DepositionSep 4, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jan 8, 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
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)69,3344
Polymers68,4662
Non-polymers8692
Water13,547752
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6672
Polymers34,2331
Non-polymers4341
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)34,6672
Polymers34,2331
Non-polymers4341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.265, 46.812, 68.797
Angle α, β, γ (deg.)89.210, 87.780, 75.170
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: 34232.840 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-Q1J / 5-bromo-N-(4-hydroxy[1,1'-biphenyl]-3-yl)-2-methoxybenzene-1-sulfonamide


Mass: 434.304 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H16BrNO4S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 752 / 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: 42.82 %
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-F / Wavelength: 0.987 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Apr 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.55→40 Å / Num. obs: 75823 / % possible obs: 91.6 % / Redundancy: 2 % / CC1/2: 0.89 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.066 / Rrim(I) all: 0.098 / Rsym value: 0.072 / Net I/σ(I): 13.3
Reflection shellResolution: 1.55→1.58 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.401 / Num. unique obs: 3936 / CC1/2: 0.68 / Rpim(I) all: 0.376 / Rrim(I) all: 0.556 / Rsym value: 0.408 / % possible all: 90.3

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DY7

6dy7


Resolution: 1.55→25.688 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 21.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.203 3666 4.84 %
Rwork0.1698 72011 -
obs0.1714 75677 91.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 64.44 Å2 / Biso mean: 21.4893 Å2 / Biso min: 12.03 Å2
Refinement stepCycle: final / Resolution: 1.55→25.688 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4692 0 52 752 5496
Biso mean--33.07 32.41 -
Num. residues----616
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.55-1.57040.26651510.2352283394
1.5704-1.59190.25411610.2226283294
1.5919-1.61460.26211430.2167288494
1.6146-1.63870.27711530.2122286894
1.6387-1.66430.23081320.2084280894
1.6643-1.69160.24651680.1978287394
1.6916-1.72080.2571350.1946280393
1.7208-1.75210.24611540.1876285194
1.7521-1.78580.25751350.1887282294
1.7858-1.82220.20871490.1806283893
1.8222-1.86180.23161690.1847280993
1.8618-1.90510.22041520.182250584
1.9051-1.95270.22961030.1752286293
1.9527-2.00550.2241200.1758283594
2.0055-2.06450.21411290.1733287194
2.0645-2.13110.21551170.1701294795
2.1311-2.20720.21891260.1788286495
2.2072-2.29560.19991380.1792245582
2.2956-2.40.21861350.1822281293
2.4-2.52640.22341430.1815284995
2.5264-2.68450.21241380.1767287394
2.6845-2.89150.18781620.1692284194
2.8915-3.1820.2141560.165287495
3.182-3.64140.15751600.1458259087
3.6414-4.58350.1623920.1345183261
4.5835-25.680.16461450.146278092
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)
10.5592-0.18560.39350.32640.00420.3449-0.0291-0.2596-0.00910.16740.00150.0472-0.13980.08180.03730.33740.02220.03270.13850.01280.1443-11.254746.84912.4339
20.51990.19760.08920.87030.04760.77580.03010.0083-0.0027-0.0035-0.0411-0.05110.04240.07570.01320.21430.0053-0.01080.14610.03020.11.126331.4787-13.2585
30.9261-0.20790.02740.6540.08111.6417-0.0194-0.0108-0.14070.0357-0.02290.07670.0245-0.17050.03090.2384-0.0203-0.01520.13850.01810.1433-15.65323.2283-11.9918
41.38350.1740.0820.6649-0.24830.97450.02960.07150.00930.05570.04810.08-0.1031-0.0378-0.04990.23770.02010.00530.12170.02080.109-16.257740.5973-6.3657
50.26820.1450.02770.07710.01940.0041-0.02520.1856-0.0538-0.12970.0083-0.0820.1371-0.0329-0.0060.35850.01130.03080.20630.02750.1571-1.447220.8589.7637
60.37980.2064-0.24111.0331-0.45680.4470.01620.0190.0229-0.07950.02540.09760.07370.0118-0.03690.24820.0106-0.02760.13330.01610.1077-19.402514.735925.8413
71.61440.65530.3920.29590.17920.9804-0.02180.0597-0.1649-0.30480.0162-0.09890.03840.1345-0.02810.3740.03270.01190.14350.020.164-9.8435-1.170924.0283
81.4901-0.0043-0.42161.21830.11350.6705-0.0785-0.0468-0.1859-0.0552-0.0467-0.15180.1753-0.01050.11090.27130.03460.02830.16760.04560.15182.43119.813119.5602
91.91930.06180.35370.7446-0.06930.60990.03720.06160.09-0.1217-0.0698-0.06350.02310.1250.01360.27410.04260.00840.16030.040.1115-4.038422.115317.0711
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 24 through 47 )A24 - 47
2X-RAY DIFFRACTION2chain 'A' and (resid 48 through 190 )A48 - 190
3X-RAY DIFFRACTION3chain 'A' and (resid 191 through 233 )A191 - 233
4X-RAY DIFFRACTION4chain 'A' and (resid 234 through 334 )A234 - 334
5X-RAY DIFFRACTION5chain 'B' and (resid 24 through 47 )B24 - 47
6X-RAY DIFFRACTION6chain 'B' and (resid 48 through 179 )B48 - 179
7X-RAY DIFFRACTION7chain 'B' and (resid 180 through 233 )B180 - 233
8X-RAY DIFFRACTION8chain 'B' and (resid 234 through 303 )B234 - 303
9X-RAY DIFFRACTION9chain 'B' and (resid 304 through 334 )B304 - 334

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