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- PDB-8bsq: Notum Inhibitor ARUK3006561 -

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Basic information

Entry
Database: PDB / ID: 8bsq
TitleNotum Inhibitor ARUK3006561
ComponentsPalmitoleoyl-protein carboxylesterase NOTUM
KeywordsHYDROLASE / Inhibitor Notum
Function / homology
Function and homology information


[Wnt protein] O-palmitoleoyl-L-serine hydrolase / protein depalmitoleylation / palmitoleyl hydrolase activity / phospholipase C activity / Release of Hh-Np from the secreting cell / regulation of bone mineralization / negative regulation of Wnt signaling pathway / Post-translational protein phosphorylation / bone development / negative regulation of canonical Wnt signaling pathway ...[Wnt protein] O-palmitoleoyl-L-serine hydrolase / protein depalmitoleylation / palmitoleyl hydrolase activity / phospholipase C activity / Release of Hh-Np from the secreting cell / regulation of bone mineralization / negative regulation of Wnt signaling pathway / Post-translational protein phosphorylation / bone development / negative regulation of canonical Wnt signaling pathway / Wnt signaling pathway / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / endoplasmic reticulum lumen / extracellular region
Similarity search - Function
Pectinacetylesterase/NOTUM / Pectinacetylesterase
Similarity search - Domain/homology
Chem-RDO / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 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 26, 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)44,6629
Polymers43,5671
Non-polymers1,0958
Water1,946108
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1380 Å2
ΔGint-53 kcal/mol
Surface area15180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.076, 71.795, 78.447
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
#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, 115 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / 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-RDO / ethyl 4-oxidanylidene-4-[4-(trifluoromethyl)-2,3-dihydroindol-1-yl]butanoate / (2R,3S,4R,5R,6R)-6-((1R,2R,3S,4R,6S)-4,6-DIAMINO-2,3-DIHYDROXYCYCLOHEXYLOXY)-5-AMINO-2-(AMINOMETHYL)-TETRAHYDRO-2H-PYRA N-3,4-DIOL / NEOMYCIN A / NEAMINE / (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-alpha-D-glucoside / (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-D-glucoside / (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-glucoside


Mass: 315.288 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H16F3NO3 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / 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: 1.94 Å3/Da / Density % sol: 36.65 %
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: I04 / Wavelength: 0.9227 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Nov 20, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9227 Å / Relative weight: 1
ReflectionResolution: 1.45→47.7 Å / Num. obs: 60886 / % possible obs: 100 % / Redundancy: 13.5 % / CC1/2: 1 / Net I/σ(I): 17.8
Reflection shellResolution: 1.45→1.47 Å / Num. unique obs: 2999 / CC1/2: 0.694

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Processing

Software
NameVersionClassification
xia2data reduction
PHENIX1.18.2refinement
xia2data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.45→39.73 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2001 3033 4.99 %
Rwork0.1926 --
obs0.193 60781 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.45→39.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2753 0 59 108 2920
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062909
X-RAY DIFFRACTIONf_angle_d0.8493963
X-RAY DIFFRACTIONf_dihedral_angle_d17.7411048
X-RAY DIFFRACTIONf_chiral_restr0.081415
X-RAY DIFFRACTIONf_plane_restr0.005505
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.45-1.470.271280.26342592X-RAY DIFFRACTION100
1.47-1.50.26371250.23512584X-RAY DIFFRACTION100
1.5-1.520.25441490.22722574X-RAY DIFFRACTION100
1.52-1.550.21721240.20812594X-RAY DIFFRACTION100
1.55-1.580.24021310.20682603X-RAY DIFFRACTION100
1.58-1.610.21311370.20282613X-RAY DIFFRACTION100
1.61-1.650.24541440.20312588X-RAY DIFFRACTION100
1.65-1.690.26921310.19862583X-RAY DIFFRACTION100
1.69-1.730.21141230.18912623X-RAY DIFFRACTION100
1.73-1.770.20071400.18672606X-RAY DIFFRACTION100
1.77-1.830.22651430.17972616X-RAY DIFFRACTION100
1.83-1.890.16481170.18122617X-RAY DIFFRACTION100
1.89-1.950.20281230.17962609X-RAY DIFFRACTION100
1.95-2.030.21381190.18132652X-RAY DIFFRACTION100
2.03-2.120.18711480.17762619X-RAY DIFFRACTION100
2.12-2.240.20531330.17972633X-RAY DIFFRACTION100
2.24-2.380.2011580.18972596X-RAY DIFFRACTION100
2.38-2.560.20831420.19242645X-RAY DIFFRACTION100
2.56-2.820.21461590.19552644X-RAY DIFFRACTION100
2.82-3.220.20991510.19572656X-RAY DIFFRACTION100
3.22-4.060.19471550.18872688X-RAY DIFFRACTION100
4.06-39.730.17051530.19832813X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 25.4859 Å / Origin y: -1.245 Å / Origin z: 2.3157 Å
111213212223313233
T0.1316 Å20.0037 Å2-0.0035 Å2-0.1563 Å2-0.0221 Å2--0.1465 Å2
L0.8103 °2-0.0227 °2-0.0926 °2-1.4148 °2-0.071 °2--0.8254 °2
S-0.0154 Å °0.0044 Å °0.042 Å °-0.0217 Å °0.0122 Å °0.0163 Å °-0.0808 Å °-0.0014 Å °0.0014 Å °
Refinement TLS groupSelection details: all

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