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- PDB-6xcg: Histone-lysine N-methyltransferase NSD2-PWWP1 with compound UNC6934 -

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Basic information

Entry
Database: PDB / ID: 6xcg
TitleHistone-lysine N-methyltransferase NSD2-PWWP1 with compound UNC6934
ComponentsHistone-lysine N-methyltransferase NSD2
KeywordsTRANSFERASE / NSD2-PWWP / Structural Genomics / Structural Genomics Consortium / SGC
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
Chem-V01 / Histone-lysine N-methyltransferase NSD2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.64 Å
AuthorsZhou, M.Q. / Dong, A. / Ingerman, L.A. / Hanley, R.P. / Bountra, C. / Arrowsmith, C.H. / Edwards, A.M. / Min, J. / Structural Genomics Consortium (SGC)
CitationJournal: Nat.Chem.Biol. / Year: 2022
Title: A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization.
Authors: Dilworth, D. / Hanley, R.P. / Ferreira de Freitas, R. / Allali-Hassani, A. / Zhou, M. / Mehta, N. / Marunde, M.R. / Ackloo, S. / Carvalho Machado, R.A. / Khalili Yazdi, A. / Owens, D.D.G. / ...Authors: Dilworth, D. / Hanley, R.P. / Ferreira de Freitas, R. / Allali-Hassani, A. / Zhou, M. / Mehta, N. / Marunde, M.R. / Ackloo, S. / Carvalho Machado, R.A. / Khalili Yazdi, A. / Owens, D.D.G. / Vu, V. / Nie, D.Y. / Alqazzaz, M. / Marcon, E. / Li, F. / Chau, I. / Bolotokova, A. / Qin, S. / Lei, M. / Liu, Y. / Szewczyk, M.M. / Dong, A. / Kazemzadeh, S. / Abramyan, T. / Popova, I.K. / Hall, N.W. / Meiners, M.J. / Cheek, M.A. / Gibson, E. / Kireev, D. / Greenblatt, J.F. / Keogh, M.C. / Min, J. / Brown, P.J. / Vedadi, M. / Arrowsmith, C.H. / Barsyte-Lovejoy, D. / James, L.I. / Schapira, M.
History
DepositionJun 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author / database_2 / struct_ncs_dom_lim
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 / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.2Oct 18, 2023Group: Refinement description / Category: pdbx_initial_refinement_model

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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
C: Histone-lysine N-methyltransferase NSD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,77012
Polymers48,1993
Non-polymers1,5719
Water10,881604
1
A: Histone-lysine N-methyltransferase NSD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,5102
Polymers16,0661
Non-polymers4431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone-lysine N-methyltransferase NSD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,6305
Polymers16,0661
Non-polymers5644
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Histone-lysine N-methyltransferase NSD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,6305
Polymers16,0661
Non-polymers5644
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.566, 49.978, 51.179
Angle α, β, γ (deg.)91.350, 91.880, 118.270
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21A

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLN / Beg label comp-ID: GLN / End auth comp-ID: SER / End label comp-ID: SER / Refine code: 2 / Auth seq-ID: 255 - 258 / Label seq-ID: 46 - 49

Dom-IDAuth asym-IDLabel asym-ID
1BB
2AA

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.564257, -0.807468, -0.172076), (0.814704, -0.578331, 0.042316), (-0.133686, -0.116314, 0.984174)-0.50403, -0.01777, -14.19856

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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: 16066.489 Da / Num. of mol.: 3 / Fragment: UNP residues 211-350
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NSD2, KIAA1090, MMSET, TRX5, WHSC1 / Plasmid: pET28-MHL / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -V2R-pRARE2
References: UniProt: O96028, [histone H3]-lysine27 N-trimethyltransferase
#2: Chemical ChemComp-V01 / N-cyclopropyl-3-oxo-N-({4-[(pyrimidin-4-yl)carbamoyl]phenyl}methyl)-3,4-dihydro-2H-1,4-benzoxazine-7-carboxamide


Mass: 443.455 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C24H21N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-UNX / UNKNOWN ATOM OR ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 604 / 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: 2.31 Å3/Da / Density % sol: 46.82 % / Mosaicity: 0.935 °
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 1.6 M ammonium sulfate, 0.01 M magnesium chloride, 0.1 M HEPES, pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN A200 / Detector: CCD / Date: May 22, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.64→50 Å / Num. obs: 49043 / % possible obs: 92.7 % / Redundancy: 5 % / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.026 / Rrim(I) all: 0.059 / Χ2: 1.529 / Net I/σ(I): 14.6 / Num. measured all: 246572
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.64-1.672.60.43622720.7630.3070.5380.986.5
1.67-1.73.20.39523330.8190.2520.4730.83588.5
1.7-1.733.90.35823150.8670.2050.4160.9488.3
1.73-1.774.60.32824470.9090.170.370.90889.4
1.77-1.815.30.28423190.9490.1370.3150.95889.8
1.81-1.855.40.23523970.9730.1110.2610.92490.1
1.85-1.895.40.23724210.9760.1120.2620.99491.2
1.89-1.945.40.16823940.9720.080.1861.39891.4
1.94-25.40.13524300.9880.0640.1491.12691.7
2-2.075.40.10524660.9920.050.1161.18992.4
2.07-2.145.40.08824520.9930.0420.0971.3192.6
2.14-2.235.40.08924560.9940.0420.0991.41593.5
2.23-2.335.40.09325050.9910.0440.1032.44494.2
2.33-2.455.40.06924750.9960.0330.0771.55294.3
2.45-2.65.40.06225300.9970.0290.0681.68194.9
2.6-2.85.40.05725190.9970.0270.0631.94795.6
2.8-3.095.40.05225340.9970.0250.0572.2596.1
3.09-3.535.40.03726000.9990.0180.0411.89997.1
3.53-4.455.20.03725610.9980.0180.0412.72597.8
4.45-505.10.03226170.9990.0160.0361.95998.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.21 Å25.55 Å
Translation3.21 Å25.55 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
SCALEPACKdata scaling
PHASER2.8.2phasing
PDB_EXTRACT3.25data extraction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5VC8

5vc8


Resolution: 1.64→25.56 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.942 / SU B: 1.937 / SU ML: 0.068 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.105 / ESU R Free: 0.108 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.222 1168 2.4 %RANDOM
Rwork0.1778 ---
obs0.1789 47761 92.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 60.19 Å2 / Biso mean: 21.766 Å2 / Biso min: 13.48 Å2
Baniso -1Baniso -2Baniso -3
1-0.19 Å20.1 Å2-0.05 Å2
2---0.12 Å2-0.53 Å2
3----0 Å2
Refinement stepCycle: final / Resolution: 1.64→25.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3149 0 105 608 3862
Biso mean--25.13 31.17 -
Num. residues----397
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0133381
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173058
X-RAY DIFFRACTIONr_angle_refined_deg1.4341.6354580
X-RAY DIFFRACTIONr_angle_other_deg1.3871.6017103
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1135401
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.6723.182154
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.9915563
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3381512
X-RAY DIFFRACTIONr_chiral_restr0.0720.2399
X-RAY DIFFRACTIONr_gen_planes_refined0.010.024139
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02745
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: B / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
18MEDIUM POSITIONAL0.060.5
24TIGHT THERMAL8.260.5
18MEDIUM THERMAL8.022
LS refinement shellResolution: 1.64→1.682 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.299 70 -
Rwork0.268 3234 -
obs--84.96 %

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