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- PDB-7uva: Crystal structure of KDM2A histone demethylase catalytic domain i... -

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Entry
Database: PDB / ID: 7uva
TitleCrystal structure of KDM2A histone demethylase catalytic domain in complex with an H3C36 peptide modified by UNC8015
Components
  • (Lysine-specific demethylase ...) x 2
  • Histone H3.2
KeywordsGENE REGULATION / demethylase / histone / inhibitor
Function / homology
Function and homology information


histone H3K36me/H3K36me2 demethylase activity / [histone H3]-dimethyl-L-lysine36 demethylase / HDMs demethylate histones / neuroepithelial cell differentiation / unmethylated CpG binding / histone H3K36 demethylase activity / negative regulation of transcription by competitive promoter binding / heart looping / histone demethylase activity / Chromatin modifying enzymes ...histone H3K36me/H3K36me2 demethylase activity / [histone H3]-dimethyl-L-lysine36 demethylase / HDMs demethylate histones / neuroepithelial cell differentiation / unmethylated CpG binding / histone H3K36 demethylase activity / negative regulation of transcription by competitive promoter binding / heart looping / histone demethylase activity / Chromatin modifying enzymes / transcription initiation-coupled chromatin remodeling / RNA Polymerase I Promoter Opening / Interleukin-7 signaling / Assembly of the ORC complex at the origin of replication / DNA methylation / Condensation of Prophase Chromosomes / HCMV Late Events / Chromatin modifications during the maternal to zygotic transition (MZT) / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / SIRT1 negatively regulates rRNA expression / PRC2 methylates histones and DNA / Defective pyroptosis / neural tube closure / HDACs deacetylate histones / RNA Polymerase I Promoter Escape / transcription coregulator activity / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / circadian regulation of gene expression / multicellular organism growth / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / NoRC negatively regulates rRNA expression / B-WICH complex positively regulates rRNA expression / HDMs demethylate histones / regulation of circadian rhythm / neuron differentiation / PKMTs methylate histone lysines / RMTs methylate histone arginines / Meiotic recombination / Pre-NOTCH Transcription and Translation / nucleosome assembly / double-strand break repair via nonhomologous end joining / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Transcriptional regulation of granulopoiesis / structural constituent of chromatin / nucleosome / RUNX1 regulates transcription of genes involved in differentiation of HSCs / chromatin organization / Factors involved in megakaryocyte development and platelet production / HATs acetylate histones / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / Estrogen-dependent gene expression / in utero embryonic development / Amyloid fiber formation / protein heterodimerization activity / negative regulation of gene expression / chromatin / positive regulation of gene expression / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / DNA binding / extracellular exosome / zinc ion binding / extracellular region / nucleoplasm / nucleus
Similarity search - Function
PHD-finger / Jumonji, helical domain / Jumonji helical domain / Leucine-rich repeat, cysteine-containing subtype / Leucine-rich repeat - CC (cysteine-containing) subfamily / F-box-like / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type profile. / F-box domain ...PHD-finger / Jumonji, helical domain / Jumonji helical domain / Leucine-rich repeat, cysteine-containing subtype / Leucine-rich repeat - CC (cysteine-containing) subfamily / F-box-like / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type profile. / F-box domain / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain / JmjC domain profile. / Zinc finger, PHD-type, conserved site / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Histone H3 signature 1. / Leucine-rich repeat domain superfamily / Zinc finger, PHD-type / PHD zinc finger / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Zinc finger, FYVE/PHD-type / Histone-fold / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
: / N-heptanoyl-N-hydroxy-beta-alanine / Lysine-specific demethylase 2A / Histone H3.2
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.98 Å
AuthorsBudziszewski, G.R. / Azzam, D.N. / Spangler, C.J. / Skrajna, A. / Foley, C.A. / James, L.I. / Frye, S.V. / McGinty, R.K.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM119999 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM133498 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)F99CA253730 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM139514 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA010305 United States
CitationJournal: Nat Chem Biol / Year: 2023
Title: Structural basis of paralog-specific KDM2A/B nucleosome recognition.
Authors: Cathy J Spangler / Aleksandra Skrajna / Caroline A Foley / Anh Nguyen / Gabrielle R Budziszewski / Dalal N Azzam / Eyla C Arteaga / Holly C Simmons / Charlotte B Smith / Nathaniel A Wesley / ...Authors: Cathy J Spangler / Aleksandra Skrajna / Caroline A Foley / Anh Nguyen / Gabrielle R Budziszewski / Dalal N Azzam / Eyla C Arteaga / Holly C Simmons / Charlotte B Smith / Nathaniel A Wesley / Emily M Wilkerson / Jeanne-Marie E McPherson / Dmitri Kireev / Lindsey I James / Stephen V Frye / Dennis Goldfarb / Robert K McGinty /
Abstract: The nucleosome acidic patch is a major interaction hub for chromatin, providing a platform for enzymes to dock and orient for nucleosome-targeted activities. To define the molecular basis of acidic ...The nucleosome acidic patch is a major interaction hub for chromatin, providing a platform for enzymes to dock and orient for nucleosome-targeted activities. To define the molecular basis of acidic patch recognition proteome wide, we performed an amino acid resolution acidic patch interactome screen. We discovered that the histone H3 lysine 36 (H3K36) demethylase KDM2A, but not its closely related paralog, KDM2B, requires the acidic patch for nucleosome binding. Despite fundamental roles in transcriptional repression in health and disease, the molecular mechanisms governing nucleosome substrate specificity of KDM2A/B, or any related JumonjiC (JmjC) domain lysine demethylase, remain unclear. We used a covalent conjugate between H3K36 and a demethylase inhibitor to solve cryogenic electron microscopy structures of KDM2A and KDM2B trapped in action on a nucleosome substrate. Our structures show that KDM2-nucleosome binding is paralog specific and facilitated by dynamic nucleosomal DNA unwrapping and histone charge shielding that mobilize the H3K36 sequence for demethylation.
History
DepositionApr 29, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 17, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Lysine-specific demethylase 2A
B: Lysine-specific demethylase 2A
C: Histone H3.2
D: Lysine-specific demethylase 2A
E: Lysine-specific demethylase 2A
F: Histone H3.2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,92210
Polymers96,3766
Non-polymers5464
Water7,728429
1
A: Lysine-specific demethylase 2A
B: Lysine-specific demethylase 2A
C: Histone H3.2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,4615
Polymers48,1883
Non-polymers2732
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5590 Å2
ΔGint-62 kcal/mol
Surface area17860 Å2
MethodPISA
2
D: Lysine-specific demethylase 2A
E: Lysine-specific demethylase 2A
F: Histone H3.2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,4615
Polymers48,1883
Non-polymers2732
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5260 Å2
ΔGint-59 kcal/mol
Surface area17890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.903, 87.054, 176.177
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Lysine-specific demethylase ... , 2 types, 4 molecules ADBE

#1: Protein Lysine-specific demethylase 2A / F-box and leucine-rich repeat protein 11 / F-box/LRR-repeat protein 11 / JmjC domain-containing ...F-box and leucine-rich repeat protein 11 / F-box/LRR-repeat protein 11 / JmjC domain-containing histone demethylation protein 1A / [Histone-H3]-lysine-36 demethylase 1A


Mass: 39162.516 Da / Num. of mol.: 2 / Fragment: UNP residues 36-364
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Kdm2a, Fbl11, Fbxl11, Jhdm1a, Kiaa1004 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): pLysS
References: UniProt: P59997, [histone H3]-dimethyl-L-lysine36 demethylase
#2: Protein Lysine-specific demethylase 2A / F-box and leucine-rich repeat protein 11 / F-box/LRR-repeat protein 11 / JmjC domain-containing ...F-box and leucine-rich repeat protein 11 / F-box/LRR-repeat protein 11 / JmjC domain-containing histone demethylation protein 1A / [Histone-H3]-lysine-36 demethylase 1A


Mass: 7665.956 Da / Num. of mol.: 2 / Fragment: UNP residues 450-517
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Kdm2a, Fbl11, Fbxl11, Jhdm1a, Kiaa1004 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): pLysS
References: UniProt: P59997, [histone H3]-dimethyl-L-lysine36 demethylase

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Protein/peptide , 1 types, 2 molecules CF

#3: Protein/peptide Histone H3.2 / H3-clustered histone 13 / H3-clustered histone 14 / H3-clustered histone 15 / Histone H3/m / Histone H3/o


Mass: 1359.576 Da / Num. of mol.: 2 / Fragment: UNP residues 30-42 / Mutation: K36C / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q71DI3

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Non-polymers , 3 types, 433 molecules

#4: Chemical ChemComp-FE / FE (III) ION / Iron


Mass: 55.845 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Fe
#5: Chemical ChemComp-OH0 / N-heptanoyl-N-hydroxy-beta-alanine


Mass: 217.262 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H19NO4 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 429 / 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: 2.22 Å3/Da / Density % sol: 44.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 100 mM Tris-Cl, pH 8.5, 150 mM lithium sulfate, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 6, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.98→88.09 Å / Num. obs: 58130 / % possible obs: 97.35 % / Redundancy: 6.3 % / Biso Wilson estimate: 36.82 Å2 / CC1/2: 0.991 / CC star: 0.998 / Rmerge(I) obs: 0.19 / Rpim(I) all: 0.09 / Rrim(I) all: 0.22 / Net I/σ(I): 6.48
Reflection shellResolution: 1.98→2.03 Å / Redundancy: 6.7 % / Num. unique obs: 4103 / CC1/2: 0.674 / % possible all: 98.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4QX7

4qx7


Resolution: 1.98→88.09 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.94 / SU B: 4.623 / SU ML: 0.128 / Cross valid method: THROUGHOUT / ESU R: 0.191 / ESU R Free: 0.173 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23701 2914 5 %RANDOM
Rwork0.18285 ---
obs0.18552 55260 97.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.473 Å2
Baniso -1Baniso -2Baniso -3
1-0.64 Å20 Å20 Å2
2--1.56 Å20 Å2
3----2.21 Å2
Refinement stepCycle: 1 / Resolution: 1.98→88.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6675 0 2 429 7106
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0196859
X-RAY DIFFRACTIONr_bond_other_d0.0060.026414
X-RAY DIFFRACTIONr_angle_refined_deg1.7641.9549290
X-RAY DIFFRACTIONr_angle_other_deg1.034314795
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2975807
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.42424.125337
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.7151193
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.8381539
X-RAY DIFFRACTIONr_chiral_restr0.1050.2994
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0217660
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021611
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.3292.7373245
X-RAY DIFFRACTIONr_mcbond_other2.3292.7383246
X-RAY DIFFRACTIONr_mcangle_it3.2524.0844045
X-RAY DIFFRACTIONr_mcangle_other3.2554.0854046
X-RAY DIFFRACTIONr_scbond_it3.6223.1623614
X-RAY DIFFRACTIONr_scbond_other3.6223.1623615
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.554.5665246
X-RAY DIFFRACTIONr_long_range_B_refined7.16622.5088028
X-RAY DIFFRACTIONr_long_range_B_other7.07722.2377877
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.98→2.031 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 203 -
Rwork0.264 4078 -
obs--98.3 %

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