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- PDB-6whn: Histone deacetylases complex with peptide macrocycles -

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Basic information

Entry
Database: PDB / ID: 6whn
TitleHistone deacetylases complex with peptide macrocycles
Components
  • Histone deacetylase 2
  • U2M-ASN-PRO-LYS-GLN-DLY-TRP-GLY peptide macrocycle
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Anchor extension / de novo design macrocycles / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


protein de-2-hydroxyisobutyrylase activity / positive regulation of male mating behavior / negative regulation of peptidyl-lysine acetylation / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol / negative regulation of MHC class II biosynthetic process ...protein de-2-hydroxyisobutyrylase activity / positive regulation of male mating behavior / negative regulation of peptidyl-lysine acetylation / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol / negative regulation of MHC class II biosynthetic process / NuRD complex / positive regulation of interleukin-1 production / regulation of cell fate specification / negative regulation of stem cell population maintenance / EGR2 and SOX10-mediated initiation of Schwann cell myelination / negative regulation of transcription by competitive promoter binding / ESC/E(Z) complex / regulation of stem cell differentiation / STAT3 nuclear events downstream of ALK signaling / cellular response to dopamine / histone deacetylase / cardiac muscle hypertrophy / protein lysine deacetylase activity / positive regulation of signaling receptor activity / response to caffeine / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / histone deacetylase activity / embryonic digit morphogenesis / positive regulation of oligodendrocyte differentiation / positive regulation of stem cell population maintenance / Sin3-type complex / Notch-HLH transcription pathway / dendrite development / eyelid development in camera-type eye / odontogenesis of dentin-containing tooth / positive regulation of proteolysis / RNA Polymerase I Transcription Initiation / response to amyloid-beta / histone deacetylase complex / hair follicle placode formation / Regulation of MECP2 expression and activity / NF-kappaB binding / positive regulation of collagen biosynthetic process / response to hyperoxia / positive regulation of epithelial to mesenchymal transition / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / heterochromatin formation / MECP2 regulates neuronal receptors and channels / cellular response to retinoic acid / positive regulation of tyrosine phosphorylation of STAT protein / Regulation of TP53 Activity through Acetylation / cellular response to transforming growth factor beta stimulus / response to amphetamine / heat shock protein binding / SUMOylation of chromatin organization proteins / negative regulation of cell migration / response to cocaine / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / response to nicotine / Regulation of PTEN gene transcription / promoter-specific chromatin binding / HDACs deacetylate histones / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / protein modification process / NoRC negatively regulates rRNA expression / negative regulation of DNA-binding transcription factor activity / NOTCH1 Intracellular Domain Regulates Transcription / cellular response to hydrogen peroxide / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / positive regulation of tumor necrosis factor production / negative regulation of neuron projection development / cellular response to heat / Factors involved in megakaryocyte development and platelet production / histone binding / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / response to lipopolysaccharide / chromosome, telomeric region / chromatin remodeling / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / chromatin binding / positive regulation of cell population proliferation / chromatin / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / RNA binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
Histone deacetylase / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.54 Å
AuthorsBera, A.K. / Hosseinzadeh, P. / Watson, P. / Baker, D.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Commun / Year: 2021
Title: Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites.
Authors: Hosseinzadeh, P. / Watson, P.R. / Craven, T.W. / Li, X. / Rettie, S. / Pardo-Avila, F. / Bera, A.K. / Mulligan, V.K. / Lu, P. / Ford, A.S. / Weitzner, B.D. / Stewart, L.J. / Moyer, A.P. / Di ...Authors: Hosseinzadeh, P. / Watson, P.R. / Craven, T.W. / Li, X. / Rettie, S. / Pardo-Avila, F. / Bera, A.K. / Mulligan, V.K. / Lu, P. / Ford, A.S. / Weitzner, B.D. / Stewart, L.J. / Moyer, A.P. / Di Piazza, M. / Whalen, J.G. / Greisen, P.J. / Christianson, D.W. / Baker, D.
History
DepositionApr 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2021Group: Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Revision 1.2Jul 28, 2021Group: 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 1.3Oct 18, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone deacetylase 2
B: Histone deacetylase 2
C: Histone deacetylase 2
F: U2M-ASN-PRO-LYS-GLN-DLY-TRP-GLY peptide macrocycle
G: U2M-ASN-PRO-LYS-GLN-DLY-TRP-GLY peptide macrocycle
H: U2M-ASN-PRO-LYS-GLN-DLY-TRP-GLY peptide macrocycle
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,32228
Polymers134,7456
Non-polymers2,57722
Water17,439968
1
A: Histone deacetylase 2
F: U2M-ASN-PRO-LYS-GLN-DLY-TRP-GLY peptide macrocycle
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,07311
Polymers44,9152
Non-polymers1,1589
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2440 Å2
ΔGint-41 kcal/mol
Surface area16770 Å2
MethodPISA
2
B: Histone deacetylase 2
G: U2M-ASN-PRO-LYS-GLN-DLY-TRP-GLY peptide macrocycle
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,7289
Polymers44,9152
Non-polymers8137
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1420 Å2
ΔGint-53 kcal/mol
Surface area16320 Å2
MethodPISA
3
C: Histone deacetylase 2
H: U2M-ASN-PRO-LYS-GLN-DLY-TRP-GLY peptide macrocycle
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,5218
Polymers44,9152
Non-polymers6066
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1410 Å2
ΔGint-53 kcal/mol
Surface area15150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.349, 97.665, 138.989
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein / Protein/peptide , 2 types, 6 molecules ABCFGH

#1: Protein Histone deacetylase 2 / / HD2


Mass: 43897.934 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92769, histone deacetylase
#2: Protein/peptide U2M-ASN-PRO-LYS-GLN-DLY-TRP-GLY peptide macrocycle


Mass: 1017.225 Da / Num. of mol.: 3 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 7 types, 990 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-NHE / 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID / N-CYCLOHEXYLTAURINE / CHES / CHES (buffer)


Mass: 207.290 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C8H17NO3S / Comment: pH buffer*YM
#6: Chemical
ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: C8H18O5 / Comment: precipitant*YM
#7: Chemical
ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: C6H14O4
#8: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C4H10O3
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 968 / 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: 2.46 Å3/Da / Density % sol: 50.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 40% (v/v) PEG600 and 100mM CHES pH 9.5

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Data collection

DiffractionMean temperature: 293 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Feb 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.54→43.82 Å / Num. obs: 183886 / % possible obs: 98.4 % / Redundancy: 7 % / Biso Wilson estimate: 16.84 Å2 / CC1/2: 0.987 / Rmerge(I) obs: 0.098 / Net I/σ(I): 17.5
Reflection shellResolution: 1.54→1.68 Å / Rmerge(I) obs: 0.731 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 17064 / CC1/2: 0.539

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Processing

Software
NameVersionClassification
PHENIX1.17rc1_3605refinement
HKL-3000data reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4lxz

4lxz


Resolution: 1.54→43.82 Å / SU ML: 0.1577 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 18.6036
RfactorNum. reflection% reflection
Rfree0.1924 9349 5.08 %
Rwork0.1628 --
obs0.1643 183886 99.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 24.19 Å2
Refinement stepCycle: LAST / Resolution: 1.54→43.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8929 0 359 975 10263
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01249607
X-RAY DIFFRACTIONf_angle_d1.231212931
X-RAY DIFFRACTIONf_chiral_restr0.07621318
X-RAY DIFFRACTIONf_plane_restr0.00881662
X-RAY DIFFRACTIONf_dihedral_angle_d19.12765731
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.54-1.560.29732390.26254627X-RAY DIFFRACTION79.51
1.56-1.580.26263370.25035751X-RAY DIFFRACTION99.82
1.58-1.60.24443320.23215778X-RAY DIFFRACTION99.92
1.6-1.620.26193080.22715806X-RAY DIFFRACTION99.9
1.62-1.640.25673250.22295797X-RAY DIFFRACTION99.79
1.64-1.660.22882920.21335804X-RAY DIFFRACTION100
1.66-1.680.26892790.2065875X-RAY DIFFRACTION99.95
1.68-1.710.23573140.1975759X-RAY DIFFRACTION99.93
1.71-1.740.22062920.19085831X-RAY DIFFRACTION99.92
1.74-1.760.22063160.18175814X-RAY DIFFRACTION99.98
1.76-1.790.1953230.16915824X-RAY DIFFRACTION99.93
1.79-1.830.21093040.17055791X-RAY DIFFRACTION99.97
1.83-1.860.18813160.1735831X-RAY DIFFRACTION99.93
1.86-1.90.22843350.18085798X-RAY DIFFRACTION100
1.9-1.940.20223180.17745808X-RAY DIFFRACTION100
1.94-1.990.20252850.17075869X-RAY DIFFRACTION100
1.99-2.040.20262910.1655883X-RAY DIFFRACTION100
2.04-2.090.1912680.16265867X-RAY DIFFRACTION100
2.09-2.150.18083010.16135859X-RAY DIFFRACTION100
2.15-2.220.19943230.16165866X-RAY DIFFRACTION100
2.22-2.30.1773400.15715822X-RAY DIFFRACTION100
2.3-2.390.18563090.15665863X-RAY DIFFRACTION100
2.39-2.50.19992890.16085896X-RAY DIFFRACTION100
2.5-2.630.18323380.15755868X-RAY DIFFRACTION100
2.63-2.80.19073510.15675860X-RAY DIFFRACTION100
2.8-3.020.1873080.165890X-RAY DIFFRACTION100
3.02-3.320.19583700.15755881X-RAY DIFFRACTION100
3.32-3.80.1733050.13785971X-RAY DIFFRACTION100
3.8-4.790.15283070.12826022X-RAY DIFFRACTION100
4.79-43.820.18283340.16726226X-RAY DIFFRACTION99.76

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