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- PDB-6nm4: Crystal structure of SAM-bound PRDM9 in complex with MRK-740 inhibitor -

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Basic information

Entry
Database: PDB / ID: 6nm4
TitleCrystal structure of SAM-bound PRDM9 in complex with MRK-740 inhibitor
ComponentsHistone-lysine N-methyltransferase PRDM9
KeywordsGENE REGULATION/INHIBITOR / PR SET domain / Lysine Methyltransferase / Inhibitor / Structural Genomics / Structural Genomics Consortium / SGC / GENE REGULATION-INHIBITOR complex
Function / homology
Function and homology information


recombination hotspot binding / positive regulation of reciprocal meiotic recombination / positive regulation of fertilization / [histone H3]-lysine9 N-trimethyltransferase / male gamete generation / histone H4K20me methyltransferase activity / meiotic gene conversion / [histone H4]-N-methyl-L-lysine20 N-methyltransferase / histone H4K20 monomethyltransferase activity / histone H3K9 trimethyltransferase activity ...recombination hotspot binding / positive regulation of reciprocal meiotic recombination / positive regulation of fertilization / [histone H3]-lysine9 N-trimethyltransferase / male gamete generation / histone H4K20me methyltransferase activity / meiotic gene conversion / [histone H4]-N-methyl-L-lysine20 N-methyltransferase / histone H4K20 monomethyltransferase activity / histone H3K9 trimethyltransferase activity / [histone H4]-lysine20 N-methyltransferase / [histone H3]-lysine36 N-trimethyltransferase / female gamete generation / histone H3K36 trimethyltransferase activity / [histone H3]-lysine4 N-trimethyltransferase / homologous chromosome pairing at meiosis / double-strand break repair involved in meiotic recombination / histone H3K4 trimethyltransferase activity / histone H3K36 methyltransferase activity / histone H3K4 methyltransferase activity / Transferases; Transferring one-carbon groups; Methyltransferases / PKMTs methylate histone lysines / Meiotic recombination / chromosome / methylation / regulation of gene expression / transcription cis-regulatory region binding / regulation of DNA-templated transcription / negative regulation of apoptotic process / protein homodimerization activity / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
PRDM7/PRDM9, PR/SET domain / : / C2H2-type zinc finger / Ancestral KRAB domain / SSXRD motif / SSXRD motif / KRAB-related domain profile. / PR domain zinc finger protein 2, PR domain / KRAB box / krueppel associated box ...PRDM7/PRDM9, PR/SET domain / : / C2H2-type zinc finger / Ancestral KRAB domain / SSXRD motif / SSXRD motif / KRAB-related domain profile. / PR domain zinc finger protein 2, PR domain / KRAB box / krueppel associated box / Krueppel-associated box / KRAB domain superfamily / Beta-clip-like / SET domain / SET domain superfamily / SET domain profile. / SET domain / Zinc finger, C2H2 type / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type / Beta Complex / Mainly Beta
Similarity search - Domain/homology
Chem-KS7 / S-ADENOSYLMETHIONINE / Histone-lysine N-methyltransferase PRDM9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.58 Å
AuthorsIvanochko, D. / Halabelian, L. / Fischer, C. / Sanders, J.M. / Kattar, S.D. / Brown, P.J. / Edwards, A.M. / Bountra, C. / Arrowsmith, C.H. / Structural Genomics Consortium (SGC)
CitationJournal: Nat Commun / Year: 2019
Title: Discovery of a chemical probe for PRDM9.
Authors: Allali-Hassani, A. / Szewczyk, M.M. / Ivanochko, D. / Organ, S.L. / Bok, J. / Ho, J.S.Y. / Gay, F.P.H. / Li, F. / Blazer, L. / Eram, M.S. / Halabelian, L. / Dilworth, D. / Luciani, G.M. / ...Authors: Allali-Hassani, A. / Szewczyk, M.M. / Ivanochko, D. / Organ, S.L. / Bok, J. / Ho, J.S.Y. / Gay, F.P.H. / Li, F. / Blazer, L. / Eram, M.S. / Halabelian, L. / Dilworth, D. / Luciani, G.M. / Lima-Fernandes, E. / Wu, Q. / Loppnau, P. / Palmer, N. / Talib, S.Z.A. / Brown, P.J. / Schapira, M. / Kaldis, P. / O'Hagan, R.C. / Guccione, E. / Barsyte-Lovejoy, D. / Arrowsmith, C.H. / Sanders, J.M. / Kattar, S.D. / Bennett, D.J. / Nicholson, B. / Vedadi, M.
History
DepositionJan 10, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 13, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2019Group: 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 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone-lysine N-methyltransferase PRDM9
B: Histone-lysine N-methyltransferase PRDM9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,46211
Polymers43,6052
Non-polymers1,8579
Water41423
1
A: Histone-lysine N-methyltransferase PRDM9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,7316
Polymers21,8021
Non-polymers9285
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone-lysine N-methyltransferase PRDM9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,7315
Polymers21,8021
Non-polymers9284
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.026, 74.800, 141.435
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: 0 / Auth seq-ID: 196 - 377 / Label seq-ID: 2 - 183

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

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Histone-lysine N-methyltransferase PRDM9 / PR domain zinc finger protein 9 / PR domain-containing protein 9


Mass: 21802.352 Da / Num. of mol.: 2 / Fragment: PR-SET domain (UNP residues 195-385)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRDM9, PFM6 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9NQV7, histone-lysine N-methyltransferase

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Non-polymers , 5 types, 32 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE / S-Adenosyl methionine


Mass: 398.437 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H22N6O5S
#4: Chemical ChemComp-KS7 / 4-[3-(3,5-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-methyl-9-(2-methylpyridin-4-yl)-1,4,9-triazaspiro[5.5]undecane


Mass: 464.560 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H32N6O3
#5: Chemical ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 3 / Source method: obtained synthetically
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 2.38 Å3/Da / Density % sol: 48.3 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Bis-Tris, pH 6.0, 0.2 M ammonium acetate, 24.5% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 24, 2018
RadiationMonochromator: Cryogenically-cooled single crystal Si(220) side bounce
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.58→39.88 Å / Num. obs: 13290 / % possible obs: 99.6 % / Redundancy: 7.3 % / CC1/2: 0.997 / Rmerge(I) obs: 0.129 / Rpim(I) all: 0.051 / Rrim(I) all: 0.139 / Net I/σ(I): 10.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.58-2.697.81.65515910.4950.6281.772100
8.94-39.886.30.0383870.9970.0170.04299.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.85 Å39.88 Å
Translation3.85 Å39.88 Å

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0218refinement
XDSdata reduction
Aimless0.6.2data scaling
PHASER2.8.2phasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4IJD

4ijd


Resolution: 2.58→39.88 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.928 / SU B: 29.499 / SU ML: 0.285 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.759 / ESU R Free: 0.336
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2581 664 5 %RANDOM
Rwork0.2072 ---
obs0.2098 12587 99.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 120.05 Å2 / Biso mean: 61.466 Å2 / Biso min: 30.37 Å2
Baniso -1Baniso -2Baniso -3
1-0.77 Å20 Å2-0 Å2
2---0.45 Å20 Å2
3----0.32 Å2
Refinement stepCycle: final / Resolution: 2.58→39.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2923 0 127 23 3073
Biso mean--70.07 42.27 -
Num. residues----368
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0193155
X-RAY DIFFRACTIONr_bond_other_d0.0010.022689
X-RAY DIFFRACTIONr_angle_refined_deg1.5371.9554298
X-RAY DIFFRACTIONr_angle_other_deg0.8213.0026238
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.95366
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.36524.065155
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.19815455
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.3081518
X-RAY DIFFRACTIONr_chiral_restr0.0870.2416
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213724
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02688
Refine LS restraints NCS

Ens-ID: 1 / Number: 5587 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.1 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.58→2.647 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.472 41 -
Rwork0.382 904 -
all-945 -
obs--99.89 %
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)
12.2705-0.35711.26750.2182-0.64542.87070.3417-0.2784-0.1427-0.159-0.03690.00460.3696-0.1835-0.30480.2165-0.0238-0.02110.15120.11490.1071-1.8246-20.55322.0176
20.4108-0.36460.28752.43341.24611.63560.0295-0.18080.0105-0.49870.08050.0673-0.17690.0286-0.110.16890.0478-0.06670.207-0.09760.073-12.29569.435212.3379
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A195 - 402
2X-RAY DIFFRACTION2B196 - 402

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