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- PDB-7b3g: Notum complex with ARUK3003902 -

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Basic information

Entry
Database: PDB / ID: 7b3g
TitleNotum complex with ARUK3003902
ComponentsPalmitoleoyl-protein carboxylesterase NOTUM
KeywordsHYDROLASE / 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 / 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 / negative regulation of canonical Wnt signaling pathway ...protein-containing complex destabilizing activity / [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 / negative regulation of canonical Wnt signaling pathway / bone development / 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-SSQ / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.28 Å
AuthorsZhao, Y. / Jone, E.Y.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity.
Authors: Steadman, D. / Atkinson, B.N. / Zhao, Y. / Willis, N.J. / Frew, S. / Monaghan, A. / Patel, C. / Armstrong, E. / Costelloe, K. / Magno, L. / Bictash, M. / Jones, E.Y. / Fish, P.V. / Svensson, F.
History
DepositionNov 30, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 21, 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 1.3Oct 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: Palmitoleoyl-protein carboxylesterase NOTUM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,09815
Polymers43,5671
Non-polymers1,53114
Water2,180121
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
  • monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2640 Å2
ΔGint-63 kcal/mol
Surface area14970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.420, 72.540, 78.065
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
#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, 134 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / 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.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-SSQ / 6-((2-chlorophenyl)thio)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one / 6-(2-chlorophenyl)sulfanyl-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one / 6-(2-chlorophenyl)sulfanyl-2~{H}-[1,2,4]triazolo[4,3-b]pyridazin-3-one


Mass: 278.717 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H7ClN4OS / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / 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: 36.3 %
Crystal growTemperature: 296 K / Method: evaporation / pH: 4.2 / Details: 1.5 M Ammonium Sulphate 0.1 M Sodium Citrate

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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: Nov 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.28→53.14 Å / Num. obs: 87567 / % possible obs: 100 % / Redundancy: 13 % / CC1/2: 1 / Net I/σ(I): 15.5
Reflection shellResolution: 1.28→1.3 Å / Num. unique obs: 4328 / CC1/2: 0.667

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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: 7ARG

7arg


Resolution: 1.28→45.97 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 21.49 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2151 4323 4.94 %
Rwork0.2023 83121 -
obs0.203 87444 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 77.01 Å2 / Biso mean: 23.1599 Å2 / Biso min: 12.37 Å2
Refinement stepCycle: final / Resolution: 1.28→45.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2728 0 87 121 2936
Biso mean--40.13 27.3 -
Num. residues----344
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.28-1.290.33221400.3272721286199
1.29-1.310.32421460.308627332879100
1.31-1.330.30211330.304627742907100
1.33-1.340.30741490.289527182867100
1.34-1.360.3371400.283527172857100
1.36-1.380.30031410.274527712912100
1.38-1.40.2791610.258427212882100
1.4-1.420.25721270.253827692896100
1.42-1.440.2671520.245727072859100
1.44-1.470.24951360.233227662902100
1.47-1.490.20071560.21627212877100
1.49-1.520.23011410.20827432884100
1.52-1.550.20151060.200128002906100
1.55-1.580.20941500.195227362886100
1.58-1.610.24181310.200827752906100
1.61-1.650.20161460.200227632909100
1.65-1.690.21221350.194427532888100
1.69-1.740.21461600.193827452905100
1.74-1.790.19771510.19327272878100
1.79-1.850.1961660.196427532919100
1.85-1.910.21681300.196127932923100
1.91-1.990.20011550.193927642919100
1.99-2.080.2331360.193727762912100
2.08-2.190.18981370.189828132950100
2.19-2.330.22491730.195727392912100
2.33-2.510.21021560.200928032959100
2.51-2.760.21751410.201328092950100
2.76-3.160.21551310.203628582989100
3.16-3.980.18651460.189728563002100
3.98-45.970.21261510.193329973148100
Refinement TLS params.Method: refined / Origin x: 25.1797 Å / Origin y: 71.4189 Å / Origin z: 80.765 Å
111213212223313233
T0.1272 Å20.002 Å2-0.001 Å2-0.1399 Å2-0.0152 Å2--0.1292 Å2
L0.5609 °2-0.1329 °20.0155 °2-0.7555 °20.0692 °2--0.5499 °2
S-0.0113 Å °0.0029 Å °0.0259 Å °-0.0224 Å °-0.0014 Å °-0.016 Å °-0.076 Å °-0.005 Å °-0 Å °
Refinement TLS groupSelection details: (chain A and resseq 87:514)

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