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- PDB-6wzw: Ash1L SET domain in complex with AS-85 -

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Basic information

Entry
Database: PDB / ID: 6wzw
TitleAsh1L SET domain in complex with AS-85
ComponentsHistone-lysine N-methyltransferase ASH1L
KeywordsPROTEIN BINDING / TRANSFERASE/INHIBITOR / Methyltransferase / complex / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


uterine gland development / tarsal gland development / histone H3K9 monomethyltransferase activity / [histone H3]-lysine36 N-trimethyltransferase / histone H3K36 trimethyltransferase activity / [histone H3]-lysine9 N-methyltransferase / uterus morphogenesis / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / flagellated sperm motility ...uterine gland development / tarsal gland development / histone H3K9 monomethyltransferase activity / [histone H3]-lysine36 N-trimethyltransferase / histone H3K36 trimethyltransferase activity / [histone H3]-lysine9 N-methyltransferase / uterus morphogenesis / histone H3K9 methyltransferase activity / histone H3K9me2 methyltransferase activity / flagellated sperm motility / histone H3K36 methyltransferase activity / histone H3K4 methyltransferase activity / histone H3 methyltransferase activity / negative regulation of MAPK cascade / negative regulation of acute inflammatory response / decidualization / bicellular tight junction / single fertilization / post-embryonic development / skeletal system development / PKMTs methylate histone lysines / chromosome / MAPK cascade / methylation / transcription by RNA polymerase II / inflammatory response / chromatin binding / regulation of DNA-templated transcription / Golgi apparatus / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / nucleus / metal ion binding
Similarity search - Function
ASH1-like, PHD finger / ASH1-like, Bromodomain / PhD finger domain / AWS domain / AWS domain / AWS domain profile. / associated with SET domains / DNA binding domain with preference for A/T rich regions / AT hook, DNA-binding motif / Bromo adjacent homology domain ...ASH1-like, PHD finger / ASH1-like, Bromodomain / PhD finger domain / AWS domain / AWS domain / AWS domain profile. / associated with SET domains / DNA binding domain with preference for A/T rich regions / AT hook, DNA-binding motif / Bromo adjacent homology domain / BAH domain / Bromo adjacent homology (BAH) domain superfamily / Bromo adjacent homology (BAH) domain / BAH domain profile. / Post-SET domain / Post-SET domain profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Zinc finger, PHD-type, conserved site / Zinc finger PHD-type signature. / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Bromodomain / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / Chem-UG7 / Histone-lysine N-methyltransferase ASH1L
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsLi, H. / Deng, J. / Cierpicki, T. / Grembecka, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA244254 United States
CitationJournal: Nat Commun / Year: 2021
Title: Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.
Authors: Rogawski, D.S. / Deng, J. / Li, H. / Miao, H. / Borkin, D. / Purohit, T. / Song, J. / Chase, J. / Li, S. / Ndoj, J. / Klossowski, S. / Kim, E. / Mao, F. / Zhou, B. / Ropa, J. / Krotoska, M.Z. ...Authors: Rogawski, D.S. / Deng, J. / Li, H. / Miao, H. / Borkin, D. / Purohit, T. / Song, J. / Chase, J. / Li, S. / Ndoj, J. / Klossowski, S. / Kim, E. / Mao, F. / Zhou, B. / Ropa, J. / Krotoska, M.Z. / Jin, Z. / Ernst, P. / Feng, X. / Huang, G. / Nishioka, K. / Kelly, S. / He, M. / Wen, B. / Sun, D. / Muntean, A. / Dou, Y. / Maillard, I. / Cierpicki, T. / Grembecka, J.
History
DepositionMay 14, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 7, 2021Provider: repository / Type: Initial release
Revision 1.1May 26, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 18, 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

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Assembly

Deposited unit
A: Histone-lysine N-methyltransferase ASH1L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,4297
Polymers26,0171
Non-polymers1,4136
Water4,612256
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.277, 31.998, 91.160
Angle α, β, γ (deg.)90.000, 102.341, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Histone-lysine N-methyltransferase ASH1L / ASH1-like protein / huASH1 / Absent small and homeotic disks protein 1 homolog / Lysine N-methyltransferase 2H


Mass: 26016.516 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ASH1L, KIAA1420, KMT2H / Production host: Escherichia coli (E. coli)
References: UniProt: Q9NR48, Transferases; Transferring one-carbon groups; Methyltransferases, [histone H3]-lysine36 N-trimethyltransferase

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Non-polymers , 5 types, 262 molecules

#2: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#3: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-UG7 / N-{[3-(3-carbamothioylphenyl)-1-{1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}-1H-indol-6-yl]methyl}azetidine-3-carboxamide


Mass: 579.657 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H28F3N5O3S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.09 Å3/Da / Density % sol: 41.11 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1 M HEPES pH 7.5, 30% 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: Jun 23, 2018
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.69→37.33 Å / Num. obs: 24518 / % possible obs: 99.6 % / Redundancy: 3.7 % / Biso Wilson estimate: 14.59 Å2 / Rmerge(I) obs: 0.105 / Rsym value: 0.105 / Net I/σ(I): 14.944
Reflection shellResolution: 1.69→1.72 Å / Rmerge(I) obs: 0.483 / Num. unique obs: 2374 / CC1/2: 0.876

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4YNM

4ynm


Resolution: 1.69→37.33 Å / SU ML: 0.1547 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.4401
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2063 2000 8.16 %
Rwork0.164 22506 -
obs0.1674 24506 99.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.43 Å2
Refinement stepCycle: LAST / Resolution: 1.69→37.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1767 0 84 256 2107
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00711915
X-RAY DIFFRACTIONf_angle_d12587
X-RAY DIFFRACTIONf_chiral_restr0.0738257
X-RAY DIFFRACTIONf_plane_restr0.0051334
X-RAY DIFFRACTIONf_dihedral_angle_d21.153779
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.69-1.730.26761370.22181545X-RAY DIFFRACTION96.83
1.73-1.780.24131420.19591593X-RAY DIFFRACTION99.03
1.78-1.830.23411370.18741542X-RAY DIFFRACTION99.53
1.83-1.890.25151460.1921637X-RAY DIFFRACTION99.66
1.89-1.960.24551410.17571588X-RAY DIFFRACTION99.88
1.96-2.030.19571400.17431583X-RAY DIFFRACTION99.88
2.03-2.130.22641460.16551626X-RAY DIFFRACTION99.94
2.13-2.240.18641400.16141583X-RAY DIFFRACTION100
2.24-2.380.19771420.16621609X-RAY DIFFRACTION99.94
2.38-2.560.22771450.17811618X-RAY DIFFRACTION100
2.56-2.820.22921430.16381609X-RAY DIFFRACTION100
2.82-3.230.20121460.15991655X-RAY DIFFRACTION100
3.23-4.070.17441450.13661626X-RAY DIFFRACTION100
4.07-37.330.18451500.15551692X-RAY DIFFRACTION99.51

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