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- PDB-7b45: Notum complex with ARUK3003934 -

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Basic information

Entry
Database: PDB / ID: 7b45
TitleNotum complex with ARUK3003934
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-SWQ / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.38 Å
AuthorsFish, P. / Jones, 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
DepositionDec 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 27, 2022Group: 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 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 13, 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)45,04814
Polymers43,5671
Non-polymers1,48013
Water2,000111
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2280 Å2
ΔGint-62 kcal/mol
Surface area15210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.793, 72.196, 78.143
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, 123 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.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-SWQ / 6-(3-methylsulfanylphenyl)sulfanyl-2~{H}-[1,2,4]triazolo[4,3-b]pyridazin-3-one


Mass: 290.364 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H10N4OS2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 111 / 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: 36.46 %
Crystal growTemperature: 296 K / Method: evaporation / 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: 1.38→53.03 Å / Num. obs: 70022 / % possible obs: 99.7 % / Redundancy: 13.2 % / CC1/2: 1 / Net I/σ(I): 18.3
Reflection shellResolution: 1.38→1.4 Å / Num. unique obs: 3388 / CC1/2: 0.668

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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: 1.38→46.05 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1941 3405 4.87 %
Rwork0.1896 66524 -
obs0.1898 69929 99.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 74.01 Å2 / Biso mean: 23.7603 Å2 / Biso min: 12.66 Å2
Refinement stepCycle: final / Resolution: 1.38→46.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2739 0 84 111 2934
Biso mean--38.55 27.29 -
Num. residues----344
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 24

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.38-1.40.27721390.2922675281498
1.4-1.420.27761330.27842741287499
1.42-1.440.26441340.25862712284699
1.44-1.470.25941380.24162726286499
1.47-1.490.24021220.23452743286599
1.49-1.520.24731220.22162750287299
1.52-1.550.23591330.20542730286399
1.55-1.580.21251580.19782724288299
1.58-1.610.2211560.19542755291199
1.61-1.650.22691360.184527262862100
1.65-1.690.1931690.188427292898100
1.69-1.740.22471440.183727502894100
1.74-1.790.2271410.179727552896100
1.79-1.850.18741550.175527502905100
1.85-1.910.20691320.181227892921100
1.91-1.990.18121570.174427502907100
1.99-2.080.20141400.172427972937100
2.08-2.190.16291330.171928012934100
2.19-2.330.20121350.17828032938100
2.33-2.510.1951570.189727872944100
2.51-2.760.18081240.191728382962100
2.76-3.160.19731430.191928372980100
3.16-3.980.17171550.18228563011100
3.98-46.050.18561490.192830003149100
Refinement TLS params.Method: refined / Origin x: 25.3601 Å / Origin y: 70.9551 Å / Origin z: 80.961 Å
111213212223313233
T0.1477 Å2-0.0001 Å2-0.0022 Å2-0.1665 Å2-0.0153 Å2--0.1528 Å2
L0.634 °2-0.0854 °2-0.0451 °2-1.0519 °2-0.0362 °2--0.6414 °2
S-0.0188 Å °0.0168 Å °0.0181 Å °-0.0203 Å °0.0059 Å °-0.0116 Å °-0.0604 Å °-0.0132 Å °0.0115 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allL1
2X-RAY DIFFRACTION1allA87 - 1801
3X-RAY DIFFRACTION1allS1 - 211
4X-RAY DIFFRACTION1allB1 - 14
5X-RAY DIFFRACTION1allC1 - 3

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