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Basic information

Entry
Database: PDB / ID: 7pk3
TitleNotum_ARUK3001185
ComponentsPalmitoleoyl-protein carboxylesterase NOTUM
KeywordsSIGNALING PROTEIN / Notum Inhibitor
Function / homology
Function and homology information


protein-containing complex destabilizing activity / [Wnt protein] O-palmitoleoyl-L-serine hydrolase / protein depalmitoleylation / palmitoleyl hydrolase activity / Release of Hh-Np from the secreting cell / C-type glycerophospholipase activity / regulation of bone mineralization / negative regulation of Wnt signaling pathway / Post-translational protein phosphorylation / negative regulation of canonical Wnt signaling pathway ...protein-containing complex destabilizing activity / [Wnt protein] O-palmitoleoyl-L-serine hydrolase / protein depalmitoleylation / palmitoleyl hydrolase activity / Release of Hh-Np from the secreting cell / C-type glycerophospholipase activity / regulation of bone mineralization / negative regulation of Wnt signaling pathway / Post-translational protein phosphorylation / negative regulation of canonical Wnt signaling pathway / bone development / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Wnt signaling pathway / endoplasmic reticulum lumen / extracellular region
Similarity search - Function
Pectinacetylesterase/NOTUM / Pectinacetylesterase
Similarity search - Domain/homology
Chem-7T0 / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.41 Å
AuthorsVecchia, L. / Hillier, J. / Zhao, Y. / Fish, P. / Jones, E.Y.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC375/A17721 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2022
Title: Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit.
Authors: Willis, N.J. / Mahy, W. / Sipthorp, J. / Zhao, Y. / Woodward, H.L. / Atkinson, B.N. / Bayle, E.D. / Svensson, F. / Frew, S. / Jeganathan, F. / Monaghan, A. / Benvegnu, S. / Jolly, S. / ...Authors: Willis, N.J. / Mahy, W. / Sipthorp, J. / Zhao, Y. / Woodward, H.L. / Atkinson, B.N. / Bayle, E.D. / Svensson, F. / Frew, S. / Jeganathan, F. / Monaghan, A. / Benvegnu, S. / Jolly, S. / Vecchia, L. / Ruza, R.R. / Kjaer, S. / Howell, S. / Snijders, A.P. / Bictash, M. / Salinas, P.C. / Vincent, J.P. / Jones, E.Y. / Whiting, P. / Fish, P.V.
History
DepositionAug 25, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 7, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 20, 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: Palmitoleoyl-protein carboxylesterase NOTUM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,6299
Polymers43,5671
Non-polymers1,0628
Water2,288127
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1420 Å2
ΔGint-54 kcal/mol
Surface area15380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.068, 71.502, 78.358
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Palmitoleoyl-protein carboxylesterase NOTUM / hNOTUM


Mass: 43567.148 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NOTUM, OK/SW-CL.30 / Production host: Homo sapiens (human)
References: UniProt: Q6P988, [Wnt protein] O-palmitoleoyl-L-serine hydrolase
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 4 types, 134 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-7T0 / 1-[2,4-bis(chloranyl)-3-(trifluoromethyl)phenyl]-1,2,3-triazole / 1-[2,4-dichloro-3-(trifluoromethyl)phenyl]triazole


Mass: 282.049 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H4Cl2F3N3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 127 / 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: 1.93 Å3/Da / Density % sol: 36.31 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop
Details: 1.5 M Ammonium Sulphate 0.1 M Sodium Citrate, pH4.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.41→71.5 Å / Num. obs: 65798 / % possible obs: 100 % / Redundancy: 12.7 % / CC1/2: 1 / Net I/σ(I): 12.5
Reflection shellResolution: 1.41→1.43 Å / Num. unique obs: 3278 / CC1/2: 0.454

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6R8P

6r8p


Resolution: 1.41→52.82 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 19.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2037 3270 4.98 %
Rwork0.1747 62436 -
obs0.1761 65706 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 88.19 Å2 / Biso mean: 24.8021 Å2 / Biso min: 12.79 Å2
Refinement stepCycle: final / Resolution: 1.41→52.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2787 0 60 127 2974
Biso mean--30.65 34.25 -
Num. residues----350
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 23 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.41-1.430.31351440.264526992843
1.43-1.450.29021690.248626392808
1.45-1.480.24871360.227526612797
1.48-1.50.24241340.208527152849
1.5-1.530.30961300.201926592789
1.53-1.560.28271300.17827102840
1.56-1.590.24841500.178926802830
1.59-1.630.19951470.166726832830
1.63-1.660.24461220.158327042826
1.66-1.710.21331540.156626932847
1.71-1.750.20961320.143626692801
1.75-1.80.18551430.142826952838
1.8-1.860.17231270.143127212848
1.86-1.930.1891410.147427032844
1.93-20.18941750.141126882863
2-2.10.17571500.146526892839
2.1-2.210.17191420.146727232865
2.21-2.340.18411480.155827242872
2.34-2.530.18581420.165127332875
2.53-2.780.21421290.178227402869
2.78-3.180.21451460.185627652911
3.18-4.010.21311330.184928142947
4.01-52.820.1941460.195329293075

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