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- PDB-5lsu: Structure of the Epigenetic Oncogene MMSET and inhibition by N-Al... -

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Basic information

Entry
Database: PDB / ID: 5lsu
TitleStructure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives
ComponentsHistone-lysine N-methyltransferase NSD2
KeywordsTRANSFERASE / lysine methyltransferase MMSET SET domain
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 / Beta-clip-like / SET domain / 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. / Beta Complex / 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 / Mainly Beta
Similarity search - Domain/homology
S-ADENOSYLMETHIONINE / Histone-lysine N-methyltransferase NSD2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.14 Å
AuthorsTisi, D. / Pathuri, P. / Heightman, T.
CitationJournal: ACS Chem. Biol. / Year: 2016
Title: Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.
Authors: Tisi, D. / Chiarparin, E. / Tamanini, E. / Pathuri, P. / Coyle, J.E. / Hold, A. / Holding, F.P. / Amin, N. / Martin, A.C. / Rich, S.J. / Berdini, V. / Yon, J. / Acklam, P. / Burke, R. / ...Authors: Tisi, D. / Chiarparin, E. / Tamanini, E. / Pathuri, P. / Coyle, J.E. / Hold, A. / Holding, F.P. / Amin, N. / Martin, A.C. / Rich, S.J. / Berdini, V. / Yon, J. / Acklam, P. / Burke, R. / Drouin, L. / Harmer, J.E. / Jeganathan, F. / van Montfort, R.L. / Newbatt, Y. / Tortorici, M. / Westlake, M. / Wood, A. / Hoelder, S. / Heightman, T.D.
History
DepositionSep 5, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 5, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Database references
Revision 1.2Jan 17, 2024Group: 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 NSD2
B: Histone-lysine N-methyltransferase NSD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,76310
Polymers57,5742
Non-polymers1,1898
Water9,512528
1
A: Histone-lysine N-methyltransferase NSD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,3825
Polymers28,7871
Non-polymers5954
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone-lysine N-methyltransferase NSD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,3825
Polymers28,7871
Non-polymers5954
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)94.583, 63.114, 81.094
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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 / NSD2 / Protein trithorax-5 / Wolf-Hirschhorn syndrome candidate 1 protein / WHSC1


Mass: 28786.850 Da / Num. of mol.: 2 / Mutation: Q975L,A978L,D1071L,G1072Q,K1073R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WHSC1, KIAA1090, MMSET, NSD2, TRX5 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: O96028, histone-lysine N-methyltransferase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H22N6O5S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 528 / Source method: isolated from a natural source / Formula: H2O

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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: 2.1 Å3/Da / Density % sol: 41.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 16.0%w/v PEG 3350, 0.1M NH4Cl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Jul 10, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.14→61.56 Å / Num. obs: 27812 / % possible obs: 99.9 % / Redundancy: 6.5 % / Biso Wilson estimate: 41.03 Å2 / Rrim(I) all: 0.158 / Net I/σ(I): 8.5
Reflection shellResolution: 2.14→2.16 Å / Mean I/σ(I) obs: 1.2 / Rrim(I) all: 1.56 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3OOI

3ooi


Resolution: 2.14→49.81 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.901 / SU R Cruickshank DPI: 0.229 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.283 / SU Rfree Blow DPI: 0.211 / SU Rfree Cruickshank DPI: 0.197
RfactorNum. reflection% reflectionSelection details
Rfree0.238 1384 5.05 %RANDOM
Rwork0.171 ---
obs0.175 27404 99.9 %-
Displacement parametersBiso mean: 53.711 Å2
Baniso -1Baniso -2Baniso -3
1--18.8303 Å20 Å20 Å2
2--6.5874 Å20 Å2
3---12.2429 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: 1 / Resolution: 2.14→49.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3562 0 60 528 4150
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0123763HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.165127HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1323SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes100HARMONIC2
X-RAY DIFFRACTIONt_gen_planes559HARMONIC16
X-RAY DIFFRACTIONt_it3763HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion6.47
X-RAY DIFFRACTIONt_other_torsion20.21
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion489SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4527SEMIHARMONIC4
LS refinement shellResolution: 2.14→2.22 Å / Rfactor Rfree error: 0 / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.28 149 5.3 %
Rwork0.243 2664 -
all0.245 2813 -
obs--99.93 %
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)
10.95730.0006-0.47052.2280.02323.63710.01250.07180.0320.3654-0.0857-0.11230.18120.30130.0732-0.05210.0376-0.0273-0.14070.0057-0.16467.285558.47812.3833
20.8748-0.58870.39584.31720.46372.48440.0450.0062-0.1076-0.1196-0.20030.54420.0555-0.16650.1553-0.1881-0.0046-0.0068-0.1348-0.0216-0.062-8.441462.949354.2972
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|973 - A|1206 }
2X-RAY DIFFRACTION2{ B|976 - B|1206 }

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