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- PDB-6r8r: Structure of the Wnt deacylase Notum in complex with isoquinoline 45 -

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Basic information

Entry
Database: PDB / ID: 6r8r
TitleStructure of the Wnt deacylase Notum in complex with isoquinoline 45
ComponentsPalmitoleoyl-protein carboxylesterase NOTUM
KeywordsHYDROLASE / Wnt signalling / NOTUM Inhibitor / Crystallographic Fragment Screen
Function / homology
Function and homology information


protein-containing complex destabilizing activity / [Wnt protein] O-palmitoleoyl-L-serine hydrolase / protein depalmitoleylation / palmitoleyl hydrolase activity / C-type glycerophospholipase 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 / C-type glycerophospholipase 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-JV8 / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.27 Å
AuthorsVecchia, L. / Zhao, Y. / Ruza, R.R. / Jones, E.Y.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Cancer Research UKC375/A17721 United Kingdom
Medical Research Council (United Kingdom)MR/M000141/1 United Kingdom
CitationJournal: Medchemcomm / Year: 2019
Title: Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen.
Authors: Atkinson, B.N. / Steadman, D. / Zhao, Y. / Sipthorp, J. / Vecchia, L. / Ruza, R.R. / Jeganathan, F. / Lines, G. / Frew, S. / Monaghan, A. / Kjær, S. / Bictash, M. / Jones, E.Y. / Fish, P.V.
History
DepositionApr 2, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 8, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.2Oct 2, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)45,86126
Polymers43,5671
Non-polymers2,29325
Water3,297183
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4560 Å2
ΔGint-42 kcal/mol
Surface area16550 Å2
Unit cell
Length a, b, c (Å)60.340, 71.720, 78.130
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 / Mutation: C330S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NOTUM, OK/SW-CL.30 / Cell line (production host): HEK293S GNTI- / 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: isolated from a genetically manipulated source
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, 207 molecules

#3: Chemical ChemComp-JV8 / ~{N}-isoquinolin-6-yl-2-(2-methylphenoxy)ethanamide


Mass: 292.332 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16N2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


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


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 183 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 36.6 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 4 / Details: 1.4 M ammonium sulphate, 0.1 M citric acid, pH 4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 1.27→24.2 Å / Num. obs: 90021 / % possible obs: 100 % / Redundancy: 13 % / Biso Wilson estimate: 16.41 Å2 / CC1/2: 0.9994 / Net I/σ(I): 13.66
Reflection shellResolution: 1.27→1.29 Å / Num. unique obs: 4441 / CC1/2: 0.5197

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Processing

Software
NameVersionClassification
PHENIX1.15rc3_3435refinement
XSCALEdata scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4UZ1

4uz1


Resolution: 1.27→24.2 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 17.31
RfactorNum. reflection% reflection
Rfree0.1777 4507 5.01 %
Rwork0.1478 --
obs0.1492 89931 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 79.52 Å2 / Biso mean: 23.2508 Å2 / Biso min: 11.47 Å2
Refinement stepCycle: final / Resolution: 1.27→24.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2893 0 136 184 3213
Biso mean--40.52 33.87 -
Num. residues----362
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
1.27-1.28440.33341600.277928533013
1.2844-1.29950.28011470.251227832930
1.2995-1.31540.29521670.242927802947
1.3154-1.3320.28241510.231428072958
1.332-1.34960.2811630.229728072970
1.3496-1.36810.28231600.230527952955
1.3681-1.38760.25231520.21528132965
1.3876-1.40830.2621470.208128462993
1.4083-1.43030.23151430.180228142957
1.4303-1.45380.21721550.165228052960
1.4538-1.47880.19441640.152928042968
1.4788-1.50570.20231730.137828132986
1.5057-1.53470.19231570.139628042961
1.5347-1.5660.2021380.128228532991
1.566-1.60.17341270.117928302957
1.6-1.63720.1381580.112428523010
1.6372-1.67820.15041400.106728392979
1.6782-1.72350.15421610.111728192980
1.7235-1.77420.17631570.113128362993
1.7742-1.83150.18751460.113828452991
1.8315-1.89690.151520.114828402992
1.8969-1.97280.18091510.120928432994
1.9728-2.06260.15971490.114328563005
2.0626-2.17130.15861480.116828693017
2.1713-2.30720.16191410.127528803021
2.3072-2.48520.19511310.136528773008
2.4852-2.7350.18631240.149929143038
2.735-3.130.17241590.152229213080
3.13-3.94070.15621580.152629283086
3.9407-24.20410.16261280.171430983226

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