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- PDB-9exy: Crystal structure of the PWWP1 domain of NSD2 bound by compound 34. -

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Basic information

Entry
Database: PDB / ID: 9exy
TitleCrystal structure of the PWWP1 domain of NSD2 bound by compound 34.
ComponentsHistone-lysine N-methyltransferase NSD2
KeywordsTRANSFERASE / Methyl transferase / inhibitor / cancer drug discovery
Function / homology
Function and homology information


atrial septum secundum morphogenesis / [histone H3]-lysine36 N-dimethyltransferase / histone H4K20 methyltransferase activity / regulation of double-strand break repair via nonhomologous end joining / histone H3K36 dimethyltransferase activity / histone H3K36 trimethyltransferase activity / positive regulation of isotype switching to IgA isotypes / regulation of establishment of protein localization / atrial septum primum morphogenesis / membranous septum morphogenesis ...atrial septum secundum morphogenesis / [histone H3]-lysine36 N-dimethyltransferase / histone H4K20 methyltransferase activity / regulation of double-strand break repair via nonhomologous end joining / histone H3K36 dimethyltransferase activity / histone H3K36 trimethyltransferase activity / positive regulation of isotype switching to IgA isotypes / regulation of establishment of protein localization / atrial septum primum morphogenesis / membranous septum morphogenesis / histone H3K36 methyltransferase activity / histone H3 methyltransferase activity / Nonhomologous End-Joining (NHEJ) / bone development / G2/M DNA damage checkpoint / PKMTs methylate histone lysines / double-strand break repair / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Processing of DNA double-strand break ends / methylation / sequence-specific DNA binding / chromatin binding / regulation of DNA-templated transcription / chromatin / nucleolus / negative regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / metal ion binding / cytoplasm
Similarity search - Function
: / : / : / : / : / : / : / : / NSD, Cys-His rich domain / NSD Cys-His rich domain ...: / : / : / : / : / : / : / : / NSD, Cys-His rich domain / NSD Cys-His rich domain / AWS domain / AWS domain / AWS domain profile. / associated with SET domains / Cysteine-rich motif following a subset of SET domains / Post-SET domain / Post-SET domain profile. / HMG (high mobility group) box / HMG boxes A and B DNA-binding domains profile. / high mobility group / High mobility group box domain / High mobility group box domain superfamily / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / Zinc finger, PHD-type, conserved site / PHD-finger / Ring finger / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, RING-type / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
: / Histone-lysine N-methyltransferase NSD2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.699 Å
AuthorsCollie, G.W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Identification of Novel Potent NSD2-PWWP1 Ligands Using Structure-Based Design and Computational Approaches.
Authors: Carlino, L. / Astles, P.C. / Ackroyd, B. / Ahmed, A. / Chan, C. / Collie, G.W. / Dale, I.L. / O'Donovan, D.H. / Fawcett, C. / di Fruscia, P. / Gohlke, A. / Guo, X. / Hao-Ru Hsu, J. / Kaplan, ...Authors: Carlino, L. / Astles, P.C. / Ackroyd, B. / Ahmed, A. / Chan, C. / Collie, G.W. / Dale, I.L. / O'Donovan, D.H. / Fawcett, C. / di Fruscia, P. / Gohlke, A. / Guo, X. / Hao-Ru Hsu, J. / Kaplan, B. / Milbradt, A.G. / Northall, S. / Petrovic, D. / Rivers, E.L. / Underwood, E. / Webb, A.
History
DepositionApr 9, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 29, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Histone-lysine N-methyltransferase NSD2
B: Histone-lysine N-methyltransferase NSD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2734
Polymers40,4382
Non-polymers8352
Water3,909217
1
A: Histone-lysine N-methyltransferase NSD2
hetero molecules


  • defined by author
  • 20.6 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)20,6362
Polymers20,2191
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone-lysine N-methyltransferase NSD2
hetero molecules


  • defined by author
  • 20.6 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)20,6362
Polymers20,2191
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66, 66, 149.672
Angle α, β, γ (deg.)90, 90, 120
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein Histone-lysine N-methyltransferase NSD2 / Multiple myeloma SET domain-containing protein / MMSET / Nuclear SET domain-containing protein 2 / ...Multiple myeloma SET domain-containing protein / MMSET / Nuclear SET domain-containing protein 2 / Protein trithorax-5 / Wolf-Hirschhorn syndrome candidate 1 protein


Mass: 20218.811 Da / Num. of mol.: 2 / Mutation: K256A, K257A, K304A, K312A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NSD2, KIAA1090, MMSET, TRX5, WHSC1 / Production host: Escherichia coli (E. coli)
References: UniProt: O96028, [histone H3]-lysine36 N-dimethyltransferase
#2: Chemical ChemComp-A1H7Z / 7-[5-methyl-3-[2-methyl-5-(piperidin-1-ylmethyl)phenyl]-1,2-oxazol-4-yl]-4~{H}-1,4-benzoxazin-3-one


Mass: 417.500 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H27N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / 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: 2.33 Å3/Da / Density % sol: 47.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: Morpheus screen, condition G9

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.7→57.16 Å / Num. obs: 41671 / % possible obs: 92.2 % / Redundancy: 8.4 % / CC1/2: 0.999 / Net I/σ(I): 11.5
Reflection shellResolution: 1.7→1.73 Å / Num. unique obs: 1719 / CC1/2: 0.364

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.699→57.16 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.946 / SU R Cruickshank DPI: 0.112 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.117 / SU Rfree Blow DPI: 0.112 / SU Rfree Cruickshank DPI: 0.108
RfactorNum. reflection% reflectionSelection details
Rfree0.2479 2031 -RANDOM
Rwork0.2214 ---
obs0.2228 38795 91.3 %-
Displacement parametersBiso mean: 41.59 Å2
Baniso -1Baniso -2Baniso -3
1--2.1919 Å20 Å20 Å2
2---2.1919 Å20 Å2
3---4.3838 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: LAST / Resolution: 1.699→57.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2150 0 62 217 2429
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092278HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.953090HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d758SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes375HARMONIC5
X-RAY DIFFRACTIONt_it2278HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion269SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2140SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.69
X-RAY DIFFRACTIONt_other_torsion14.5
LS refinement shellResolution: 1.7→1.75 Å
RfactorNum. reflection% reflection
Rfree0.4312 52 -
Rwork0.395 --
obs0.3974 776 22.92 %

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