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- PDB-8bt0: Notum Inhibitor ARUK3005518 -

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Basic information

Entry
Database: PDB / ID: 8bt0
TitleNotum Inhibitor ARUK3005518
ComponentsPalmitoleoyl-protein carboxylesterase NOTUM
KeywordsHYDROLASE / Inhibitor Notum
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-RGO / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsZhao, Y. / Jones, E.Y. / Fish, P.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC375/A17721 United Kingdom
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity.
Authors: Atkinson, B.N. / Willis, N.J. / Zhao, Y. / Patel, C. / Frew, S. / Costelloe, K. / Magno, L. / Svensson, F. / Jones, E.Y. / Fish, P.V.
History
DepositionNov 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 14, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2023Group: Refinement description / Category: pdbx_initial_refinement_model / Item: _pdbx_initial_refinement_model.source_name
Revision 1.2Jun 28, 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 1.3Oct 16, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Palmitoleoyl-protein carboxylesterase NOTUM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,83214
Polymers43,5671
Non-polymers1,26513
Water1,838102
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.851, 71.540, 78.103
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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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
#2: 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 , 5 types, 114 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-RGO / (3~{a}~{S})-2,2-bis(fluoranyl)-3~{a},4-dihydro-3~{H}-pyrrolo[1,2-a]indol-1-one


Mass: 209.192 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H9F2NO / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 102 / 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: 1.92 Å3/Da / Density % sol: 35.9 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop / pH: 4.2
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: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Dec 2, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.6→59.85 Å / Num. obs: 44986 / % possible obs: 100 % / Redundancy: 13.4 % / CC1/2: 1 / Net I/σ(I): 15.7
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 2171 / CC1/2: 0.851

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Processing

Software
NameVersionClassification
PHENIX1.18.2refinement
xia2data reduction
xia2data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→52.75 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 19.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2149 2211 4.92 %
Rwork0.1889 --
obs0.1902 44904 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.6→52.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2823 0 77 102 3002
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083005
X-RAY DIFFRACTIONf_angle_d1.1724082
X-RAY DIFFRACTIONf_dihedral_angle_d26.781421
X-RAY DIFFRACTIONf_chiral_restr0.064427
X-RAY DIFFRACTIONf_plane_restr0.007523
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.630.26351350.23492568X-RAY DIFFRACTION98
1.63-1.670.22441290.21372642X-RAY DIFFRACTION100
1.67-1.710.26851390.20432633X-RAY DIFFRACTION100
1.71-1.760.22231340.19572654X-RAY DIFFRACTION100
1.76-1.810.24951300.19142634X-RAY DIFFRACTION100
1.81-1.870.24021440.18812632X-RAY DIFFRACTION100
1.87-1.940.20461310.18642659X-RAY DIFFRACTION100
1.94-2.020.23451550.18122618X-RAY DIFFRACTION100
2.02-2.110.24061400.17812658X-RAY DIFFRACTION100
2.11-2.220.20691500.17982654X-RAY DIFFRACTION100
2.22-2.360.21031370.17872654X-RAY DIFFRACTION100
2.36-2.540.20321420.1862672X-RAY DIFFRACTION100
2.54-2.790.20811320.19022696X-RAY DIFFRACTION100
2.79-3.20.21911350.1922709X-RAY DIFFRACTION100
3.2-4.030.21461340.18522743X-RAY DIFFRACTION100
4.03-52.750.19591440.19242867X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -4.8578 Å / Origin y: 1.4016 Å / Origin z: -2.5673 Å
111213212223313233
T0.1326 Å2-0.0003 Å2-0.0025 Å2-0.1514 Å2-0.0148 Å2--0.1413 Å2
L0.5812 °20.0249 °20.0527 °2-0.8082 °2-0.156 °2--0.5761 °2
S-0.0124 Å °0.0148 Å °-0.0149 Å °-0.0076 Å °0.0019 Å °0.0155 Å °0.0321 Å °0.0057 Å °0.0087 Å °
Refinement TLS groupSelection details: all

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