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- PDB-6yuy: STRUCTURE OF THE WNT DEACYLASE NOTUM IN COMPLEX WITH A PYRROLE-3-... -

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Basic information

Entry
Database: PDB / ID: 6yuy
TitleSTRUCTURE OF THE WNT DEACYLASE NOTUM IN COMPLEX WITH A PYRROLE-3-CARBOXYLIC ACID FRAGMENT 471
ComponentsPalmitoleoyl-protein carboxylesterase NOTUM
KeywordsHYDROLASE / Wnt / Wnt signalling / Frizzled / Fzd / Fragment screen / Notum
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-PQH / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsHillier, J. / Ruza, R.R. / Jones, E.Y.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
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
DepositionApr 27, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 6, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 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 / _entity.pdbx_description ..._chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.2Aug 26, 2020Group: Database references / Structure summary / Category: chem_comp / citation / citation_author
Item: _chem_comp.pdbx_synonyms / _citation.country ..._chem_comp.pdbx_synonyms / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Sep 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 1.4Jan 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 1.5Oct 16, 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)45,59720
Polymers43,5671
Non-polymers2,02919
Water2,108117
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3230 Å2
ΔGint-190 kcal/mol
Surface area15600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.400, 73.080, 78.580
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 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human)
References: UniProt: Q6P988, [Wnt protein] O-palmitoleoyl-L-serine hydrolase
#5: 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 , 4 types, 135 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-PQH / 2-methyl-5-(trifluoromethyl)-1~{H}-pyrrole-3-carboxylic acid


Mass: 193.123 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H6F3NO2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 117 / 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: 1.96 Å3/Da / Density % sol: 37.16 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 4 / Details: 1.4 M AMMONIUM SULPHATE, 0.1 M CITRIC ACID, PH 4.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 1.68→73.15 Å / Num. obs: 39826 / % possible obs: 100 % / Redundancy: 12.2 % / Biso Wilson estimate: 34.27 Å2 / CC1/2: 1 / Rrim(I) all: 0.088 / Net I/σ(I): 13.8
Reflection shellResolution: 1.68→1.71 Å / Num. unique obs: 1936 / CC1/2: 0.8 / Rrim(I) all: 1.666 / % possible all: 99.4

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Processing

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

4uz1


Resolution: 2→36.54 Å / SU ML: 0.2535 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.9264
RfactorNum. reflection% reflection
Rfree0.2308 1179 4.99 %
Rwork0.1944 --
obs0.1963 23627 99.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 42.77 Å2
Refinement stepCycle: LAST / Resolution: 2→36.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2825 0 111 117 3053
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00833055
X-RAY DIFFRACTIONf_angle_d0.88334173
X-RAY DIFFRACTIONf_chiral_restr0.0571432
X-RAY DIFFRACTIONf_plane_restr0.0057539
X-RAY DIFFRACTIONf_dihedral_angle_d21.53121101
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.090.31181340.23762765X-RAY DIFFRACTION99.76
2.09-2.20.27711620.21492760X-RAY DIFFRACTION99.86
2.2-2.340.3331260.22052712X-RAY DIFFRACTION96.86
2.34-2.520.27041330.20122786X-RAY DIFFRACTION99.97
2.52-2.770.23211650.21082777X-RAY DIFFRACTION99.97
2.77-3.170.24241340.20182848X-RAY DIFFRACTION100
3.17-40.20511670.18152823X-RAY DIFFRACTION99.73
4-36.540.21221580.18172977X-RAY DIFFRACTION99.97

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