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

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Basic information

Entry
Database: PDB / ID: 6whq
TitleHistone deacetylases complex with peptide macrocycles
Components
  • Histone deacetylase 2
  • U2M-ASN-PRO-GLU-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


positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / negative regulation of dendritic spine development / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol / NuRD complex ...positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / negative regulation of dendritic spine development / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol / NuRD complex / positive regulation of interleukin-1 production / regulation of cell fate specification / EGR2 and SOX10-mediated initiation of Schwann cell myelination / negative regulation of transcription by competitive promoter binding / negative regulation of stem cell population maintenance / histone deacetylase activity, hydrolytic mechanism / ESC/E(Z) complex / histone deacetylase / regulation of stem cell differentiation / cardiac muscle hypertrophy / cellular response to dopamine / STAT3 nuclear events downstream of ALK signaling / response to caffeine / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / embryonic digit morphogenesis / histone deacetylase activity / positive regulation of intracellular estrogen receptor signaling pathway / Notch-HLH transcription pathway / Sin3-type complex / eyelid development in camera-type eye / odontogenesis of dentin-containing tooth / positive regulation of stem cell population maintenance / dendrite development / response to amyloid-beta / histone deacetylase complex / RNA Polymerase I Transcription Initiation / positive regulation of oligodendrocyte differentiation / positive regulation of proteolysis / Regulation of MECP2 expression and activity / progesterone receptor signaling pathway / hair follicle placode formation / response to hyperoxia / NF-kappaB binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / cellular response to transforming growth factor beta stimulus / positive regulation of epithelial to mesenchymal transition / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / MECP2 regulates neuronal receptors and channels / Regulation of TP53 Activity through Acetylation / cellular response to retinoic acid / heat shock protein binding / negative regulation of cell migration / SUMOylation of chromatin organization proteins / response to amphetamine / Regulation of PTEN gene transcription / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / transcription coregulator binding / Regulation of endogenous retroelements by KRAB-ZFP proteins / response to nicotine / response to cocaine / HDACs deacetylate histones / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / promoter-specific chromatin binding / circadian regulation of gene expression / negative regulation of transforming growth factor beta receptor signaling pathway / NoRC negatively regulates rRNA expression / NOTCH1 Intracellular Domain Regulates Transcription / protein modification process / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / cellular response to hydrogen peroxide / positive regulation of tumor necrosis factor production / heterochromatin formation / negative regulation of neuron projection development / cellular response to heat / Factors involved in megakaryocyte development and platelet production / response to lipopolysaccharide / histone binding / Potential therapeutics for SARS / RNA polymerase II-specific DNA-binding transcription factor binding / chromosome, telomeric region / chromatin remodeling / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / chromatin binding / negative regulation of apoptotic process / chromatin / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / 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
TRIETHYLENE GLYCOL / Histone deacetylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 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 / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
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
Revision 1.5Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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-GLU-GLN-DLY-TRP-GLY peptide macrocycle
G: U2M-ASN-PRO-GLU-GLN-DLY-TRP-GLY peptide macrocycle
H: U2M-ASN-PRO-GLU-GLN-DLY-TRP-GLY peptide macrocycle
hetero molecules


Theoretical massNumber of molelcules
Total (without water)136,62024
Polymers134,7456
Non-polymers1,87518
Water8,791488
1
A: Histone deacetylase 2
F: U2M-ASN-PRO-GLU-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 area1680 Å2
ΔGint-48 kcal/mol
Surface area16540 Å2
MethodPISA
2
B: Histone deacetylase 2
G: U2M-ASN-PRO-GLU-GLN-DLY-TRP-GLY peptide macrocycle
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,5658
Polymers44,9152
Non-polymers6506
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1530 Å2
ΔGint-49 kcal/mol
Surface area15670 Å2
MethodPISA
3
C: Histone deacetylase 2
H: U2M-ASN-PRO-GLU-GLN-DLY-TRP-GLY peptide macrocycle
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3277
Polymers44,9152
Non-polymers4125
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1010 Å2
ΔGint-56 kcal/mol
Surface area15450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.442, 97.301, 138.637
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-GLU-GLN-DLY-TRP-GLY peptide macrocycle


Mass: 1017.159 Da / Num. of mol.: 3 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 6 types, 506 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


Mass: 207.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H17NO3S / Comment: pH buffer*YM
#6: Chemical
ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C6H14O4
#7: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 488 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 48.34 %
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: 0.97648 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: 0.97648 Å / Relative weight: 1
ReflectionResolution: 2.35→48.65 Å / Num. obs: 52747 / % possible obs: 100 % / Redundancy: 7.4 % / Biso Wilson estimate: 40.34 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.185 / Net I/σ(I): 10
Reflection shellResolution: 2.35→2.42 Å / Redundancy: 7.5 % / Rmerge(I) obs: 1.652 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 4539 / CC1/2: 0.574 / % possible all: 100

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Processing

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

4lxz


Resolution: 2.35→48.65 Å / SU ML: 0.3256 / Cross valid method: FREE R-VALUE / σ(F): 0.31 / Phase error: 26.2292
RfactorNum. reflection% reflection
Rfree0.2413 2613 4.95 %
Rwork0.1955 --
obs0.1979 52747 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 50.62 Å2
Refinement stepCycle: LAST / Resolution: 2.35→48.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8897 0 294 495 9686
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00189464
X-RAY DIFFRACTIONf_angle_d0.455612741
X-RAY DIFFRACTIONf_chiral_restr0.04071299
X-RAY DIFFRACTIONf_plane_restr0.00311643
X-RAY DIFFRACTIONf_dihedral_angle_d15.88725626
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.35-2.390.35571180.31342599X-RAY DIFFRACTION99.93
2.39-2.440.30541300.2942630X-RAY DIFFRACTION99.96
2.44-2.490.33141410.28562596X-RAY DIFFRACTION100
2.49-2.540.30581060.262608X-RAY DIFFRACTION100
2.54-2.60.38111260.2612613X-RAY DIFFRACTION100
2.6-2.670.32511400.25482609X-RAY DIFFRACTION100
2.67-2.740.29681340.24352599X-RAY DIFFRACTION99.96
2.74-2.820.30451390.2262628X-RAY DIFFRACTION100
2.82-2.910.25881280.22222625X-RAY DIFFRACTION100
2.91-3.010.27431450.22952615X-RAY DIFFRACTION100
3.01-3.140.27921430.21612622X-RAY DIFFRACTION99.96
3.14-3.280.28241440.21342625X-RAY DIFFRACTION99.96
3.28-3.450.22061250.19762640X-RAY DIFFRACTION100
3.45-3.670.25351310.17892640X-RAY DIFFRACTION99.96
3.67-3.950.22581450.15862654X-RAY DIFFRACTION100
3.95-4.350.18951310.14382668X-RAY DIFFRACTION100
4.35-4.980.17931750.14182646X-RAY DIFFRACTION100
4.98-6.270.23191440.17812702X-RAY DIFFRACTION100
6.27-48.650.20621680.18722815X-RAY DIFFRACTION99.9

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