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- PDB-7zyu: HDAC6 ZnF domain inhibitor - DARPin (Designed Ankyrin repeat prot... -

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Basic information

Entry
Database: PDB / ID: 7zyu
TitleHDAC6 ZnF domain inhibitor - DARPin (Designed Ankyrin repeat protein) F10
Components
  • Designed Ankyrin repeat protein F10
  • Histone deacetylase 6
KeywordsDE NOVO PROTEIN / Darpin / zinc finger
Function / homology
Function and homology information


negative regulation of hydrogen peroxide metabolic process / cellular response to topologically incorrect protein / polyubiquitinated misfolded protein transport / positive regulation of cellular response to oxidative stress / erythrocyte enucleation / negative regulation of aggrephagy / positive regulation of cholangiocyte proliferation / response to misfolded protein / negative regulation of oxidoreductase activity / regulation of microtubule-based movement ...negative regulation of hydrogen peroxide metabolic process / cellular response to topologically incorrect protein / polyubiquitinated misfolded protein transport / positive regulation of cellular response to oxidative stress / erythrocyte enucleation / negative regulation of aggrephagy / positive regulation of cholangiocyte proliferation / response to misfolded protein / negative regulation of oxidoreductase activity / regulation of microtubule-based movement / parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization / negative regulation of protein-containing complex disassembly / protein-containing complex disassembly / negative regulation of axon extension involved in axon guidance / regulation of establishment of protein localization / positive regulation of tubulin deacetylation / tubulin deacetylation / regulation of autophagy of mitochondrion / Cilium Assembly / peptidyl-lysine deacetylation / tubulin deacetylase activity / collateral sprouting / Transcriptional regulation by RUNX2 / lysosome localization / negative regulation of protein acetylation / misfolded protein binding / negative regulation of microtubule depolymerization / ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway / protein deacetylation / cilium disassembly / response to growth factor / dendritic spine morphogenesis / histone deacetylase / aggresome assembly / regulation of androgen receptor signaling pathway / protein lysine deacetylase activity / positive regulation of signaling receptor activity / cellular response to misfolded protein / aggresome / cellular response to parathyroid hormone stimulus / positive regulation of dendrite morphogenesis / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / regulation of fat cell differentiation / microtubule associated complex / negative regulation of gene expression, epigenetic / histone deacetylase activity / response to corticosterone / dynein complex binding / axonal transport of mitochondrion / Notch-HLH transcription pathway / positive regulation of epithelial cell migration / cell leading edge / beta-tubulin binding / response to dexamethasone / protein quality control for misfolded or incompletely synthesized proteins / RUNX2 regulates osteoblast differentiation / histone deacetylase complex / response to immobilization stress / alpha-tubulin binding / cilium assembly / HSF1 activation / polyubiquitin modification-dependent protein binding / regulation of macroautophagy / negative regulation of protein-containing complex assembly / inclusion body / axon cytoplasm / response to amphetamine / multivesicular body / positive regulation of synaptic transmission, glutamatergic / transcription corepressor binding / ciliary basal body / ubiquitin binding / regulation of autophagy / caveola / negative regulation of proteolysis / actin filament organization / intracellular protein transport / Late endosomal microautophagy / Hsp90 protein binding / protein destabilization / regulation of protein stability / tau protein binding / NOTCH1 Intracellular Domain Regulates Transcription / beta-catenin binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / autophagy / histone deacetylase binding / Aggrephagy / Chaperone Mediated Autophagy / cellular response to hydrogen peroxide / protein polyubiquitination / positive regulation of peptidyl-serine phosphorylation / actin binding / cellular response to heat / microtubule binding / perikaryon / microtubule / RNA polymerase II cis-regulatory region sequence-specific DNA binding / axon
Similarity search - Function
Ubiquitin Carboxyl-terminal Hydrolase-like zinc finger / Zinc finger, UBP-type / Zn-finger in ubiquitin-hydrolases and other protein / Zinc finger UBP-type profile. / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Histone deacetylase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsWang, L. / Kempf, G.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation2014/264 Switzerland
Citation
Journal: Cell Rep / Year: 2022
Title: Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways.
Authors: Wang, L. / Moreira, E.A. / Kempf, G. / Miyake, Y. / Oliveira Esteves, B.I. / Fahmi, A. / Schaefer, J.V. / Dreier, B. / Yamauchi, Y. / Alves, M.P. / Pluckthun, A. / Matthias, P.
#1: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2012
Title: Towards automated crystallographic structure refinement with phenix.refine.
Authors: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D.
History
DepositionMay 25, 2022Deposition site: PDBE / Processing site: PDBE
SupersessionJun 1, 2022ID: 7ATT
Revision 1.0Jun 1, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Mar 27, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone deacetylase 6
B: Designed Ankyrin repeat protein F10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,8348
Polymers29,4522
Non-polymers3826
Water18010
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2440 Å2
ΔGint2 kcal/mol
Surface area12390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.391, 81.391, 103.644
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z
Components on special symmetry positions
IDModelComponents
11B-306-

HOH

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Components

#1: Protein Histone deacetylase 6 / HD6 / Tubulin-lysine deacetylase HDAC6


Mass: 12279.010 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC6, KIAA0901, JM21 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9UBN7, histone deacetylase, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Protein Designed Ankyrin repeat protein F10


Mass: 17172.498 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3) (bacteria)
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 3.35 Å3/Da / Density % sol: 63.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 3.6 M sodium formate, Bis-Tris 0.1M pH=6.7, 10% w/v Glycerol, 30% w/v 1,8-Diaminooctane(additive).

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 11, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.43→58.29 Å / Num. obs: 11398 / % possible obs: 94.4 % / Redundancy: 10.5 % / Biso Wilson estimate: 64.61 Å2 / CC1/2: 0.999 / Net I/σ(I): 19
Reflection shellResolution: 2.431→2.632 Å / Num. unique obs: 572 / CC1/2: 0.589

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Processing

Software
NameVersionClassification
PHENIX1.19.1refinement
autoPROCdata reduction
STARANISOdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3gv4

3gv4


Resolution: 2.43→58.29 Å / SU ML: 0.2433 / Cross valid method: FREE R-VALUE / σ(F): 1.92 / Phase error: 34.0046
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2498 1071 5.06 %
Rwork0.2166 20108 -
obs0.2184 11396 73.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 78.11 Å2
Refinement stepCycle: LAST / Resolution: 2.43→58.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2029 0 15 10 2054
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00342085
X-RAY DIFFRACTIONf_angle_d0.5892835
X-RAY DIFFRACTIONf_chiral_restr0.0426318
X-RAY DIFFRACTIONf_plane_restr0.0035373
X-RAY DIFFRACTIONf_dihedral_angle_d9.4652739
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.43-2.540.342100.4158371X-RAY DIFFRACTION10.6
2.54-2.680.4514480.3678986X-RAY DIFFRACTION29.36
2.68-2.840.3751940.34491822X-RAY DIFFRACTION52.44
2.84-3.060.41111820.31013237X-RAY DIFFRACTION94.03
3.06-3.370.29591590.30683447X-RAY DIFFRACTION100
3.37-3.860.26192020.22823400X-RAY DIFFRACTION100
3.86-4.860.20311750.17743435X-RAY DIFFRACTION99.97
4.86-58.290.21582010.17013410X-RAY DIFFRACTION99.92
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)
13.00309096137-2.04812826092.614869473833.54336803968-1.913248165854.32893451736-0.6883253955610.237212594691.07993842838-0.335348400328-0.0351714039659-0.289711637241-0.433025871770.6193633507230.3906203609870.2390220331470.506287034282-0.671695690624-0.9321960927250.868970776503-0.1583276516257.1413012668453.960219660818.5552693706
22.373608485210.833605692862.685383080210.3236636208220.6759860550279.523149834090.522605287877-0.4492496372940.675415170749-0.208064052623-0.501260873657-0.885982648927-0.89929819591-0.8408353645770.1579043488770.6071209404420.122319614572-0.09737622799020.4335798128530.0003613275828290.52625787311712.128467584864.863483579517.4630747758
30.5470646226010.6047438012320.07319744858391.372450056220.1089508462990.365548697271-0.211051863761-0.1421652194810.603495505605-0.512881042065-0.236725971135-2.28620437335-0.1492132409720.709428989521-0.2371327070990.5167866012390.0541584267544-0.184811499020.9162516076750.2994263295350.94410373474729.701443309462.549092552124.8877468695
40.207922434866-0.296891034533-0.1813240710630.7186335727350.02912270212910.4006252178991.308512178950.5649196086370.3046463420010.82435990691-0.810833654857-0.7113247880310.4596056151790.7833435587050.00905052018090.804070159038-0.0769005155858-0.4293844359350.6352506380130.2182800936930.92684979788425.79630906257.508500245434.1695534406
50.350118887782-0.29330677066-0.3654313784230.3601325004620.3714499198450.257168916489-0.0694080592301-0.283316795855-0.01550373050020.474639508308-0.264587872443-0.741768029361-0.368920078644-0.100245699624-0.006457518839680.491379167035-0.13653699469-0.2296834456780.5100803736190.1993291964740.59428972529519.765190854464.64883379530.9877283698
60.2941297491850.0648603858268-0.7166622640340.0142963198613-0.336915099734.665306018240.09955515797980.186748849184-0.142756929230.3006017818810.548415281656-1.179429372060.512972146036-0.642791022746-0.08195942693540.433507472590.13033389204-0.2711055169850.3629083486830.09105460818110.88350125911122.197545047253.802790812125.6268772937
70.700257000982-0.332194659977-1.692439228070.3398452011731.333498123375.59387177241-0.409319431246-0.7719655521160.314450098352-0.350157386770.6031067164930.675833716621.20668039417-0.411123741567-0.1006932635760.4615828616330.0380466447302-0.1424537472720.3271359780570.1389166601310.6030510902310.179393273261.002352882826.8891807394
80.1526873643590.127706879287-0.07484330189530.378276190077-0.2773576138250.171094620842-0.2416223757310.20916563895-0.931479361891-0.337992492050.0982486625295-0.7619253620680.627277629468-0.125655397242-0.0001072772782890.667358910470.176335599088-0.07429744835860.5133928948310.05077334741070.6723499348820.217861947155.136407335716.2891491997
90.07134828292160.006877486740210.05196362959790.07629388378610.02422982456040.029093349619-0.221498246481-0.882177255986-0.383443609471-0.226456675019-0.699062855763-0.7475166882680.1955822859310.154538822638.11828837809E-50.7985188943310.516639600194-0.02500609222420.9365501411970.3161961898191.2646874173629.665195004748.536244493617.5761664787
100.161514240092-0.06916607453960.1312111012350.26615838169-0.1471368433620.117523391489-0.6900662043130.4092163225950.5056729771530.7393826106270.135410450459-1.04543295419-0.9922151198930.924972528599-0.00125006411611.606589472990.0188240908357-0.2704143114490.856754394417-0.2079061979080.88127694102513.221545838571.573626281952.738496751
110.1152761512220.1364032721620.2409498735920.1785705547930.3578022953140.8229846112830.2438472798930.1550812899650.9454191110180.647303716061-0.9779580769770.2196556159970.357791302016-0.715442327754-0.003747881239461.680251513740.347776634523-0.04074397726250.7737797774790.03982960781641.213281881295.4020643933873.28773998255.2534141422
120.187247763463-0.06855002203550.02121600838920.684594170195-0.2303980395761.07094846201-0.4619744512940.08662332955620.3931991078770.5890013881650.257928518824-0.042962562886-0.4653841660910.277300722594-0.004102131764790.7696712559690.116935792014-0.2097412551570.3934402928250.03303783724070.5289601469779.2368815700560.643401897447.2058263435
139.051401986712.543133413270.06892808649310.6921693505850.09657137413271.32380715752-0.7784894628141.230602339920.1364905640571.267223384720.7662569361350.208792724452-0.883361257842-0.239152185481-0.1513578038710.7192670791930.2894969083420.03540333002930.5113938257380.05409596910580.5116242221619.6660472768550.920030715753.3170644299
141.137630977551.69414466365-0.5828942082334.94790154463-0.5577580187660.368000980793-0.3505177757520.3696958197190.0222655584798-1.490844414980.576432964931-0.5853298939540.226168771246-0.6450687026270.2576790825650.2326924362120.127078897178-0.3142742810930.5648453467970.2618620977360.410862216546.1264774574450.319122234937.6755890759
150.249665708666-0.4260028622510.02770269159230.8784714321520.6271273585880.533922450436-0.1776611728950.136263660316-0.01578902104460.6259624702120.228309197606-0.0484722193547-0.04816267537740.003603965496721.66076311536E-60.4907615632680.0473685733659-0.04173830871870.4877071037360.08140203258310.36662665509814.45342267744.131656424744.1439773237
160.721851945890.8080165864170.6396706556130.6730008697370.5368921873140.386382057273-0.01650671920670.108805652749-0.198567444467-0.2708316843910.1829381914680.2654157422850.3290773340420.4699163679945.04375507508E-60.5066091309690.029518241069-0.04143238739490.626536499370.09416465226280.42898267224211.615516901540.998352444335.4219242822
171.066624569651.102977191840.1484528767781.314765393980.2462744485260.2748316439860.826357769136-0.0241519661614-0.340684610599-0.0775564578513-0.4907764716620.2469652685050.4461504386980.8353161026550.03617734590380.4596069181970.1919658724390.02537259161320.5611505777350.04582206000510.4360571305921.780910247137.017584167341.1130938106
180.07689164986950.0185685777629-0.07308347425810.0154202726242-0.003370729603480.1078040136530.4416988097210.3127884788280.624283432570.257126380717-0.527156383626-0.02343501025640.89169371823-0.2513821152487.4137182076E-60.648669398149-0.04762783776270.0441103016490.576989977961-0.1125189156950.55611111467610.453362006829.18875354741.7999678483
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain A and resid 1106:1112)AA1106 - 11121 - 7
22(chain A and resid 1113:1119)AA1113 - 11198 - 14
33(chain A and resid 1120:1135)AA1120 - 113515 - 30
44(chain A and resid 1136:1144)AA1136 - 114431 - 39
55(chain A and resid 1145:1173)AA1145 - 117340 - 68
66(chain A and resid 1174:1181)AA1174 - 118169 - 76
77(chain A and resid 1182:1188)AA1182 - 118877 - 83
88(chain A and resid 1189:1203)AA1189 - 120384 - 98
99(chain A and resid 1204:1212)AA1204 - 121299 - 107
1010(chain B and resid 3:21)BF3 - 211 - 19
1111(chain B and resid 22:30)BF22 - 3020 - 28
1212(chain B and resid 31:80)BF31 - 8029 - 78
1313(chain B and resid 81:94)BF81 - 9479 - 92
1414(chain B and resid 95:102)BF95 - 10293 - 100
1515(chain B and resid 103:124)BF103 - 124101 - 122
1616(chain B and resid 125:144)BF125 - 144123 - 142
1717(chain B and resid 145:154)BF145 - 154143 - 152
1818(chain B and resid 155:162)BF155 - 162153 - 160

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