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- PDB-7b50: Notum complex with ARUK3003778 -

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Basic information

Entry
Database: PDB / ID: 7b50
TitleNotum complex with ARUK3003778
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-SXQ / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.33 Å
AuthorsJones, 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
DepositionDec 3, 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 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

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Assembly

Deposited unit
A: Palmitoleoyl-protein carboxylesterase NOTUM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,59510
Polymers43,5671
Non-polymers1,0289
Water1,874104
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1470 Å2
ΔGint-46 kcal/mol
Surface area14840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.340, 72.874, 77.901
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#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: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-SXQ / 3-(3,4-dichlorophenyl)sulfanyl-1$l^{4},2,7,8-tetrazabicyclo[4.3.0]nona-1(6),2,4,7-tetraen-9-one


Mass: 313.163 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H6Cl2N4OS / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 104 / Source method: isolated from a natural source / Formula: H2O
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: 1.93 Å3/Da / Density % sol: 36.37 %
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: 1.33→47.2 Å / Num. obs: 78198 / % possible obs: 100 % / Redundancy: 20 % / CC1/2: 1 / Net I/σ(I): 11.8
Reflection shellResolution: 1.33→1.35 Å / Num. unique obs: 3817 / CC1/2: 0.725

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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: 1.33→46.01 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2051 3933 5.04 %
Rwork0.2008 74175 -
obs0.201 78108 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 68.79 Å2 / Biso mean: 24.1392 Å2 / Biso min: 13.54 Å2
Refinement stepCycle: final / Resolution: 1.33→46.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2677 0 56 104 2837
Biso mean--35.84 27.79 -
Num. residues----343
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 28

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.33-1.350.34641170.34322599271699
1.35-1.360.36011530.338125982751100
1.36-1.380.35671280.308726302758100
1.38-1.40.34091370.303326252762100
1.4-1.420.3531560.300626122768100
1.42-1.440.28911460.268426082754100
1.44-1.460.30011380.257326272765100
1.46-1.490.27711370.233326202757100
1.49-1.510.23361410.217226172758100
1.51-1.540.2241380.198926062744100
1.54-1.570.21431310.198226352766100
1.57-1.60.20591300.190126512781100
1.6-1.640.22411350.189126252760100
1.64-1.680.21051390.178526342773100
1.68-1.720.25021260.183726622788100
1.72-1.760.19481340.180426152749100
1.76-1.820.19561470.186326652812100
1.82-1.870.21981390.190526462785100
1.87-1.940.22571350.178426442779100
1.94-2.020.17931290.183826622791100
2.02-2.110.2141800.183826132793100
2.11-2.220.18091460.182626672813100
2.22-2.360.23221320.194726682800100
2.36-2.540.2091560.201226722828100
2.54-2.80.21971420.205926792821100
2.8-3.210.19561400.205726962836100
3.21-4.040.16491440.190327392883100
4.04-46.010.18141570.20128603017100
Refinement TLS params.Method: refined / Origin x: 24.9027 Å / Origin y: 71.5657 Å / Origin z: 80.9732 Å
111213212223313233
T0.1287 Å20.0028 Å2-0.0073 Å2-0.1423 Å2-0.0171 Å2--0.1331 Å2
L0.7881 °2-0.0692 °2-0.0912 °2-1.3292 °20.0828 °2--0.8063 °2
S-0.0181 Å °0.0227 Å °0.03 Å °-0.0324 Å °0.0065 Å °-0.0254 Å °-0.092 Å °0.0067 Å °0.0121 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA87 - 2501
2X-RAY DIFFRACTION1allS6 - 233
3X-RAY DIFFRACTION1allB1 - 3

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