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- PDB-6yxi: Structure of Notum in complex with a 1-(3-Chlorophenyl)-2,5-dimet... -

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Basic information

Entry
Database: PDB / ID: 6yxi
TitleStructure of Notum in complex with a 1-(3-Chlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid inhibitor
ComponentsPalmitoleoyl-protein carboxylesterase NOTUM
KeywordsHYDROLASE / Inhibitor / Complex / Wnt pathway
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 / negative regulation of canonical Wnt signaling pathway / bone development ...[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-PZ8 / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.34 Å
AuthorsVecchia, L. / Jones, E.Y. / Ruza, R.R. / Hillier, J. / Zhao, Y.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/M000141/1 United Kingdom
Cancer Research UKC375/A17721 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2020
Title: Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity.
Authors: Mahy, W. / Patel, M. / Steadman, D. / Woodward, H.L. / Atkinson, B.N. / Svensson, F. / Willis, N.J. / Flint, A. / Papatheodorou, D. / Zhao, Y. / Vecchia, L. / Ruza, R.R. / Hillier, J. / ...Authors: Mahy, W. / Patel, M. / Steadman, D. / Woodward, H.L. / Atkinson, B.N. / Svensson, F. / Willis, N.J. / Flint, A. / Papatheodorou, D. / Zhao, Y. / Vecchia, L. / Ruza, R.R. / Hillier, J. / Frew, S. / Monaghan, A. / Costa, A. / Bictash, M. / Walter, M.W. / Jones, E.Y. / Fish, P.V.
History
DepositionMay 1, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Sep 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Nov 6, 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

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Assembly

Deposited unit
A: Palmitoleoyl-protein carboxylesterase NOTUM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,91313
Polymers43,5671
Non-polymers1,34612
Water3,567198
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2220 Å2
ΔGint-72 kcal/mol
Surface area16270 Å2
Unit cell
Length a, b, c (Å)59.520, 72.160, 77.930
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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 / 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: 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, 209 molecules

#2: Chemical ChemComp-PZ8 / 1-(3-chlorophenyl)-2,5-dimethyl-pyrrole-3-carboxylic acid


Mass: 249.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H12ClNO2 / Feature type: SUBJECT OF INVESTIGATION
#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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: SO4
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 198 / 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: 2.09 Å3/Da / Density % sol: 41.18 %
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: 0.979499 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Apr 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979499 Å / Relative weight: 1
ReflectionResolution: 1.34→59.52 Å / Num. obs: 75943 / % possible obs: 99.97 % / Redundancy: 12.1 % / Biso Wilson estimate: 19.85 Å2 / CC1/2: 1 / Net I/σ(I): 17.6
Reflection shellResolution: 1.34→1.36 Å / Num. unique obs: 3714 / CC1/2: 0.555

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Processing

Software
NameVersionClassification
PHENIXdev_3699refinement
PHENIXdev_3699refinement
xia2data processing
XSCALEdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4UZ1

4uz1


Resolution: 1.34→52.95 Å / SU ML: 0.1519 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.3836
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1855 3828 5.05 %
Rwork0.1587 72038 -
obs0.1601 75866 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.51 Å2
Refinement stepCycle: LAST / Resolution: 1.34→52.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2816 0 78 198 3092
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00563075
X-RAY DIFFRACTIONf_angle_d0.78574187
X-RAY DIFFRACTIONf_chiral_restr0.0799436
X-RAY DIFFRACTIONf_plane_restr0.0059551
X-RAY DIFFRACTIONf_dihedral_angle_d18.81021132
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.34-1.360.33071390.27662603X-RAY DIFFRACTION99.35
1.36-1.370.30621320.25812625X-RAY DIFFRACTION99.46
1.37-1.390.31381380.23152642X-RAY DIFFRACTION99.96
1.39-1.410.31721490.21722643X-RAY DIFFRACTION100
1.41-1.430.24911490.20542604X-RAY DIFFRACTION99.96
1.43-1.460.24461440.18032644X-RAY DIFFRACTION99.93
1.46-1.480.22351380.17042654X-RAY DIFFRACTION99.96
1.48-1.510.21241400.15422653X-RAY DIFFRACTION99.89
1.51-1.530.19181340.14652657X-RAY DIFFRACTION99.86
1.53-1.560.20121440.13842641X-RAY DIFFRACTION99.86
1.56-1.60.19431240.13772642X-RAY DIFFRACTION99.96
1.6-1.630.20891370.12822623X-RAY DIFFRACTION99.82
1.63-1.670.17831390.12722662X-RAY DIFFRACTION99.82
1.67-1.710.17581290.13272654X-RAY DIFFRACTION99.86
1.71-1.760.17461360.12362676X-RAY DIFFRACTION99.82
1.76-1.810.17421460.1292671X-RAY DIFFRACTION99.93
1.81-1.870.19241420.132638X-RAY DIFFRACTION99.89
1.87-1.930.16151340.13532679X-RAY DIFFRACTION99.82
1.93-2.010.15751270.13642676X-RAY DIFFRACTION99.86
2.01-2.10.16361750.14112642X-RAY DIFFRACTION99.86
2.1-2.210.15791530.13522670X-RAY DIFFRACTION99.93
2.21-2.350.1861340.14722686X-RAY DIFFRACTION100
2.35-2.530.17031530.1522700X-RAY DIFFRACTION99.96
2.53-2.790.18761520.16882687X-RAY DIFFRACTION99.93
2.79-3.190.20531390.17152721X-RAY DIFFRACTION100
3.19-4.020.19551440.15892766X-RAY DIFFRACTION100
4.02-52.950.16771570.17882879X-RAY DIFFRACTION99.93

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