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- PDB-6u8l: Discovery and optimization of salicyclic acid-derived sulfonamide... -

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Basic information

Entry
Database: PDB / ID: 6u8l
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 / transcription factor TFIID complex / RNA polymerase II general transcription initiation factor activity / 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
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-Q1P / Chem-Q1S / WD repeat-containing protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.57 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 5, 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)68,6036
Polymers66,9842
Non-polymers1,6194
Water12,214678
1
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3023
Polymers33,4921
Non-polymers8102
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)34,3023
Polymers33,4921
Non-polymers8102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)134.650, 47.082, 113.052
Angle α, β, γ (deg.)90.000, 117.910, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resseq 31:57 or resseq 59:77 or resseq...
21(chain B and (resseq 31:57 or resseq 59:77 or resseq...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resseq 31:57 or resseq 59:77 or resseq...A31 - 57
121(chain A and (resseq 31:57 or resseq 59:77 or resseq...A59 - 77
131(chain A and (resseq 31:57 or resseq 59:77 or resseq...A79 - 83
141(chain A and (resseq 31:57 or resseq 59:77 or resseq...A85 - 86
151(chain A and (resseq 31:57 or resseq 59:77 or resseq...A92
161(chain A and (resseq 31:57 or resseq 59:77 or resseq...A98 - 96
171(chain A and (resseq 31:57 or resseq 59:77 or resseq...A0
181(chain A and (resseq 31:57 or resseq 59:77 or resseq...A31 - 334
191(chain A and (resseq 31:57 or resseq 59:77 or resseq...A18 - 11922
1101(chain A and (resseq 31:57 or resseq 59:77 or resseq...A31 - 334
1111(chain A and (resseq 31:57 or resseq 59:77 or resseq...A124 - 139
1121(chain A and (resseq 31:57 or resseq 59:77 or resseq...A0
1131(chain A and (resseq 31:57 or resseq 59:77 or resseq...A196 - 24
1141(chain A and (resseq 31:57 or resseq 59:77 or resseq...A196 - 203
1151(chain A and (resseq 31:57 or resseq 59:77 or resseq...A205 - 206
1161(chain A and (resseq 31:57 or resseq 59:77 or resseq...A208 - 210
1171(chain A and (resseq 31:57 or resseq 59:77 or resseq...A211
1181(chain A and (resseq 31:57 or resseq 59:77 or resseq...A31 - 334
1191(chain A and (resseq 31:57 or resseq 59:77 or resseq...A31 - 334
1201(chain A and (resseq 31:57 or resseq 59:77 or resseq...A31 - 334
1211(chain A and (resseq 31:57 or resseq 59:77 or resseq...A31 - 334
211(chain B and (resseq 31:57 or resseq 59:77 or resseq...B31 - 57
221(chain B and (resseq 31:57 or resseq 59:77 or resseq...B59 - 77
231(chain B and (resseq 31:57 or resseq 59:77 or resseq...B79 - 83
241(chain B and (resseq 31:57 or resseq 59:77 or resseq...B85 - 86
251(chain B and (resseq 31:57 or resseq 59:77 or resseq...B31 - 334
261(chain B and (resseq 31:57 or resseq 59:77 or resseq...B92
271(chain B and (resseq 31:57 or resseq 59:77 or resseq...B98 - 96
281(chain B and (resseq 31:57 or resseq 59:77 or resseq...B91 - 116
291(chain B and (resseq 31:57 or resseq 59:77 or resseq...B0
2101(chain B and (resseq 31:57 or resseq 59:77 or resseq...B141 - 153
2111(chain B and (resseq 31:57 or resseq 59:77 or resseq...B159
2121(chain B and (resseq 31:57 or resseq 59:77 or resseq...B159
2131(chain B and (resseq 31:57 or resseq 59:77 or resseq...B31 - 334
2141(chain B and (resseq 31:57 or resseq 59:77 or resseq...B31 - 334
2151(chain B and (resseq 31:57 or resseq 59:77 or resseq...B31 - 334
2161(chain B and (resseq 31:57 or resseq 59:77 or resseq...B31 - 334

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Components

#1: Protein WD repeat-containing protein 5 / BMP2-induced 3-kb gene protein


Mass: 33492.020 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-Q1P / 3-{[(5-bromo-2-hydroxyphenyl)sulfonyl]amino}-5-cyclopropyl-6-fluoro-2-hydroxybenzoic acid


Mass: 446.245 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H13BrFNO6S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-Q1S / N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]isoquinolin-1-amine


Mass: 363.413 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C20H21N5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 678 / 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: 2.36 Å3/Da / Density % sol: 47.96 %
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: Aug 21, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.57→40 Å / Num. obs: 87085 / % possible obs: 98.8 % / Redundancy: 4 % / CC1/2: 0.92 / Rmerge(I) obs: 0.073 / Rpim(I) all: 0.052 / Rrim(I) all: 0.105 / Rsym value: 0.091 / Net I/σ(I): 24.8
Reflection shellResolution: 1.57→1.6 Å / Rmerge(I) obs: 0.431 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 4335 / CC1/2: 0.865 / Rpim(I) all: 0.301 / Rrim(I) all: 0.616 / Rsym value: 0.535

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DY7

6dy7


Resolution: 1.57→26.506 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.97 / Phase error: 19.56
RfactorNum. reflection% reflection
Rfree0.1756 4160 4.78 %
Rwork0.1514 --
obs0.1526 87005 98.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 60.17 Å2 / Biso mean: 25.324 Å2 / Biso min: 11.76 Å2
Refinement stepCycle: final / Resolution: 1.57→26.506 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4664 0 106 678 5448
Biso mean--28.36 36.09 -
Num. residues----608
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0055087
X-RAY DIFFRACTIONf_angle_d0.8356952
X-RAY DIFFRACTIONf_chiral_restr0.059765
X-RAY DIFFRACTIONf_plane_restr0.005867
X-RAY DIFFRACTIONf_dihedral_angle_d14.5553014
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2466X-RAY DIFFRACTION4.161TORSIONAL
12B2466X-RAY DIFFRACTION4.161TORSIONAL
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.57-1.58360.27411160.2237244888
1.5836-1.60220.2711570.22462737100
1.6022-1.62180.25991510.20722830100
1.6218-1.64230.23691440.19942722100
1.6423-1.66390.23641510.19022826100
1.6639-1.68670.23991160.18262794100
1.6867-1.71080.22011230.17162795100
1.7108-1.73630.20311590.16932811100
1.7363-1.76340.21161400.16382717100
1.7634-1.79230.21131340.15392810100
1.7923-1.82320.21590.15692796100
1.8232-1.85640.18791400.1472772100
1.8564-1.89210.19341270.15072820100
1.8921-1.93070.18091440.14852764100
1.9307-1.97260.17521430.15072806100
1.9726-2.01850.18341300.14592793100
2.0185-2.0690.19331620.14692763100
2.069-2.12490.17561180.1536282499
2.1249-2.18740.21121180.1552806100
2.1874-2.2580.17481590.14912791100
2.258-2.33860.19371190.1597278499
2.3386-2.43220.17161210.15132810100
2.4322-2.54280.18321580.15642813100
2.5428-2.67670.18191480.15812797100
2.6767-2.84430.18341590.15432794100
2.8443-3.06360.14691380.15772846100
3.0636-3.37130.17611490.1441281699
3.3713-3.85790.17331220.1411227281
3.8579-4.85560.11471190.1193255189
4.8556-26.50.14081360.1466293799

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