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- PDB-6u6w: Discovery and optimization of salicyclic acid-derived sulfonamide... -

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Basic information

Entry
Database: PDB / ID: 6u6w
TitleDiscovery and optimization of salicyclic acid-derived sulfonamide inhibitors of the WDR5:MYC protein-protein interaction
ComponentsWD repeat-containing protein 5
KeywordsTRANSCRIPTION/INHIBITOR / WDR5 / MYC / RBBP5 / structure-based design / high-throughput screening / TRANSCRIPTION-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 / MLL1 complex / regulation of embryonic development / regulation of cell division / 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 / Activation of anterior HOX genes in hindbrain development during early embryogenesis / RMTs methylate histone arginines / 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 / 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-Q0Y / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 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
DepositionAug 30, 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)69,2514
Polymers68,4662
Non-polymers7852
Water16,592921
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6252
Polymers34,2331
Non-polymers3931
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)34,6252
Polymers34,2331
Non-polymers3931
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.247, 46.604, 68.822
Angle α, β, γ (deg.)89.92, 91.69, 104.88
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-Q0Y / 5-bromo-N-(5-chloro-2-hydroxyphenyl)-2-methoxybenzene-1-sulfonamide


Mass: 392.653 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H11BrClNO4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 921 / 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: 2.14 Å3/Da / Density % sol: 42.41 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: Bis-Tris pH 6.5, 0.2M ammonium acetate, PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9786 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 9, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.2→40 Å / Num. obs: 159898 / % possible obs: 90 % / Redundancy: 2.1 % / Biso Wilson estimate: 10.45 Å2 / CC1/2: 0.92 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.065 / Rrim(I) all: 0.097 / Rsym value: 0.071 / Net I/σ(I): 15.1
Reflection shellResolution: 1.2→1.22 Å / Redundancy: 1.7 % / Rmerge(I) obs: 0.351 / Num. unique obs: 7832 / CC1/2: 0.795 / Rpim(I) all: 0.243 / Rrim(I) all: 0.361 / Rsym value: 0.265 / % possible all: 87.4

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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: 1.2→25.5 Å / SU ML: 0.1 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 17.06
RfactorNum. reflection% reflection
Rfree0.179 7873 4.93 %
Rwork0.16 --
obs0.161 159762 90 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 14.53 Å2
Refinement stepCycle: LAST / Resolution: 1.2→25.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4728 0 42 921 5691
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2-1.21360.23972610.2134945X-RAY DIFFRACTION87
1.2136-1.22790.22932520.20814963X-RAY DIFFRACTION88
1.2279-1.24290.22672650.20625108X-RAY DIFFRACTION90
1.2429-1.25860.21082530.20315107X-RAY DIFFRACTION91
1.2586-1.27520.20552990.18935104X-RAY DIFFRACTION91
1.2752-1.29270.21212980.18745120X-RAY DIFFRACTION92
1.2927-1.31110.22372790.18695163X-RAY DIFFRACTION92
1.3111-1.33070.20112500.17575246X-RAY DIFFRACTION92
1.3307-1.35150.19982510.17865167X-RAY DIFFRACTION92
1.3515-1.37360.19542450.16965253X-RAY DIFFRACTION93
1.3736-1.39730.19232700.16955206X-RAY DIFFRACTION93
1.3973-1.42270.17752720.15945222X-RAY DIFFRACTION93
1.4227-1.45010.16292600.15985252X-RAY DIFFRACTION93
1.4501-1.47970.17122860.15865260X-RAY DIFFRACTION93
1.4797-1.51190.17872500.15815310X-RAY DIFFRACTION93
1.5119-1.5470.19882490.16035262X-RAY DIFFRACTION94
1.547-1.58570.17572670.1525292X-RAY DIFFRACTION94
1.5857-1.62860.17413190.14925262X-RAY DIFFRACTION94
1.6286-1.67650.17583070.14915277X-RAY DIFFRACTION94
1.6765-1.73060.16742500.14795358X-RAY DIFFRACTION95
1.7306-1.79240.17412660.15085348X-RAY DIFFRACTION95
1.7924-1.86420.18963110.15715264X-RAY DIFFRACTION95
1.8642-1.9490.17881970.15144116X-RAY DIFFRACTION73
1.949-2.05170.16372750.15075406X-RAY DIFFRACTION96
2.0517-2.18020.18412720.15395342X-RAY DIFFRACTION95
2.1802-2.34840.17431910.16323324X-RAY DIFFRACTION59
2.3484-2.58450.1892540.16945491X-RAY DIFFRACTION97
2.5845-2.9580.16943020.16415473X-RAY DIFFRACTION98
2.958-3.72490.16622200.15164296X-RAY DIFFRACTION77
3.7249-25.4920.16222020.1473952X-RAY DIFFRACTION73
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)
10.0434-0.0453-0.03140.03660.01890.01070.18470.02980.1369-0.26450.1660.00390.1146-0.2004-0.08570.2785-0.0909-0.00160.25460.04660.18693.5141-9.8966-2.6086
20.53010.13820.2870.4845-0.22750.34470.00350.1095-0.0247-0.0916-0.016-0.09080.12320.0361-0.0020.08760.01080.01780.1021-0.00570.084524.3142-14.52819.0625
30.5642-0.0123-0.5740.8104-0.84572.2250.03290.07290.02810.013-0.0148-0.0225-0.08270.06450.03910.05710.00450.00260.09680.00350.084327.0194-3.682624.5319
41.6057-0.2948-1.220.97230.07931.6520.0493-0.020.02050.0112-0.02-0.0972-0.01050.1235-0.00830.05880.0017-0.00860.09650.00270.089932.3296-1.381428.3155
51.479-0.0296-0.24580.93480.02672.38420.0276-0.00430.02370.0231-0.0128-0.0211-0.0351-0.0473-0.01260.05140.00980.0120.06160.00110.084722.20994.017527.2563
62.6329-0.1267-1.11790.63990.13311.51850.0020.00120.09640.02250.0103-0.1438-0.03660.1134-0.01080.0864-0.00120.00770.0926-0.00130.106823.46939.101331.1666
70.79440.2317-1.07980.7263-0.14172.6990.01940.04720.0881-0.06980.02730.038-0.0822-0.0786-0.05750.07280.0080.00410.0857-0.00080.088613.75147.068524.6905
81.12961.0312-0.7362.4582-1.42872.0491-0.0179-0.05860.0847-0.12050.00760.09870.0017-0.1051-0.00850.09980.01720.01040.0991-0.01190.12669.034911.775527.2492
91.47970.5891-0.67031.7211-0.90052.8382-0.00690.0910.1617-0.1470.10690.0910.0291-0.1965-0.03360.0686-0.00730.00150.07180.00690.10215.93372.386320.8764
101.0085-0.18870.05110.99070.50120.70270.0089-0.04790.09590.00910.04530.0814-0.0709-0.0152-0.0380.0838-0.01090.00350.09590.01240.11123.0743-3.144320.2347
111.3332-0.3520.12471.1341-0.3211.3726-0.0150.0095-0.1073-0.06450.06140.11260.0876-0.0243-0.05990.0857-0.0193-0.00330.08610.00280.08914.2583-14.141917.2648
121.10230.17340.15831.4098-0.52460.9097-0.065-0.003-0.0481-0.07950.08860.00370.1394-0.0702-0.01370.08710.00030.00390.1056-0.01130.075115.4399-15.779116.9254
130.43160.0430.14310.5070.04130.37090.0564-0.0699-0.01860.1345-0.03070.01670.0384-0.0308-0.0150.107-0.02130.00810.08090.00240.07297.528610.0965-8.3924
140.82720.1157-0.1011.0425-0.2961.04610.0077-0.00780.01440.04340.00070.06920.0238-0.03660.00850.0699-0.00210.01190.062-0.0020.07533.703426.4189-16.3563
151.2288-0.8773-0.13650.9432-0.09020.6924-0.0467-0.0790.16860.09140.0479-0.0976-0.04930.0966-0.00630.106-0.008-0.00230.0959-0.00620.127114.073232.7232-12.8263
160.87660.29550.17120.9919-0.14830.98650.0303-0.02310.02810.1087-0.0159-0.05040.0141-0.052-0.01050.0982-0.015-0.01040.0853-0.00170.077923.095117.7332-6.6173
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 24 THROUGH 33 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 34 THROUGH 84 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 85 THROUGH 106 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 107 THROUGH 126 )
5X-RAY DIFFRACTION5CHAIN 'A' AND (RESID 127 THROUGH 148 )
6X-RAY DIFFRACTION6CHAIN 'A' AND (RESID 149 THROUGH 167 )
7X-RAY DIFFRACTION7CHAIN 'A' AND (RESID 168 THROUGH 190 )
8X-RAY DIFFRACTION8CHAIN 'A' AND (RESID 191 THROUGH 210 )
9X-RAY DIFFRACTION9CHAIN 'A' AND (RESID 213 THROUGH 233 )
10X-RAY DIFFRACTION10CHAIN 'A' AND (RESID 234 THROUGH 272 )
11X-RAY DIFFRACTION11CHAIN 'A' AND (RESID 273 THROUGH 303 )
12X-RAY DIFFRACTION12CHAIN 'A' AND (RESID 304 THROUGH 334 )
13X-RAY DIFFRACTION13CHAIN 'B' AND (RESID 24 THROUGH 126 )
14X-RAY DIFFRACTION14CHAIN 'B' AND (RESID 127 THROUGH 190 )
15X-RAY DIFFRACTION15CHAIN 'B' AND (RESID 191 THROUGH 233 )
16X-RAY DIFFRACTION16CHAIN 'B' AND (RESID 234 THROUGH 334 )

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