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- PDB-7b3h: Notum complex with ARUK3003909 -

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Basic information

Entry
Database: PDB / ID: 7b3h
TitleNotum complex with ARUK3003909
ComponentsPalmitoleoyl-protein carboxylesterase NOTUM
KeywordsHYDROLASE / Notum Inhibitor
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-SSW / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.28 Å
AuthorsZhao, Y. / Jones, E.Y. / Fish, P.
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 1.3Nov 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)44,73612
Polymers43,5671
Non-polymers1,16911
Water2,324129
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
  • monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2000 Å2
ΔGint-61 kcal/mol
Surface area15060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.313, 72.909, 77.993
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 , 1 types, 1 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

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Non-polymers , 5 types, 140 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-SSW / 6-((3-(trifluoromethoxy)phenyl)thio)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one / 6-[3-(trifluoromethyloxy)phenyl]sulfanyl-2~{H}-[1,2,4]triazolo[4,3-b]pyridazin-3-one / 6-[3-(trifluoromethyloxy)phenyl]sulfanyl-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one


Mass: 328.270 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H7F3N4O2S / 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.: 129 / 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: 36.45 %
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→47.21 Å / Num. obs: 87738 / % possible obs: 100 % / Redundancy: 13 % / CC1/2: 1 / Net I/σ(I): 16
Reflection shellResolution: 1.28→1.3 Å / Num. unique obs: 4351 / CC1/2: 0.744

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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→46.01 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 18.85 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2038 4334 4.94 %
Rwork0.195 83320 -
obs0.1955 87654 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 63.87 Å2 / Biso mean: 20.9757 Å2 / Biso min: 11.59 Å2
Refinement stepCycle: final / Resolution: 1.28→46.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2740 0 68 129 2937
Biso mean--31.45 25.7 -
Num. residues----343
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.28-1.290.28031370.280627262863
1.29-1.310.28091490.26827392888
1.31-1.330.23511280.260427892917
1.33-1.340.27841570.250227402897
1.34-1.360.2581420.246127222864
1.36-1.380.25541320.236327772909
1.38-1.40.26621580.223527022860
1.4-1.420.23821410.225127792920
1.42-1.440.2261460.210627372883
1.44-1.470.2291390.202127592898
1.47-1.490.21111580.193327462904
1.49-1.520.23461390.187227482887
1.52-1.550.19281120.178527982910
1.55-1.580.17821420.177327202862
1.58-1.610.20551390.173327762915
1.61-1.650.18171390.183127822921
1.65-1.690.18271380.176327872925
1.69-1.740.18671560.175527272883
1.74-1.790.16191560.177527642920
1.79-1.850.18351610.181827482909
1.85-1.910.19991340.185327742908
1.91-1.990.18671560.17527692925
1.99-2.080.20451370.179427942931
2.08-2.190.16481360.179428272963
2.19-2.330.21091750.190227452920
2.33-2.510.2181550.195527962951
2.51-2.760.2041400.202628232963
2.76-3.160.21011340.19928562990
3.16-3.980.19351450.196128693014
3.98-46.010.20871530.230013154
Refinement TLS params.Method: refined / Origin x: 25.1553 Å / Origin y: 71.5013 Å / Origin z: 80.7474 Å
111213212223313233
T0.1306 Å20.0006 Å2-0.0041 Å2-0.1413 Å2-0.0121 Å2--0.133 Å2
L0.6097 °2-0.122 °2-0.0985 °2-0.7278 °20.0567 °2--0.511 °2
S-0.0115 Å °0.0029 Å °0.0294 Å °-0.0276 Å °-0.0006 Å °-0.0206 Å °-0.0648 Å °0.0044 Å °0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA88 - 451
2X-RAY DIFFRACTION1allA601 - 729
3X-RAY DIFFRACTION1allA509 - 511

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