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- PDB-6t2h: Furano[2,3-d]prymidine amides as Notum inhibitors -

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Basic information

Entry
Database: PDB / ID: 6t2h
TitleFurano[2,3-d]prymidine amides as Notum inhibitors
ComponentsPalmitoleoyl-protein carboxylesterase NOTUM
KeywordsHYDROLASE / substrate
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 / bone development / negative regulation of canonical Wnt signaling pathway ...[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 / bone development / negative regulation of canonical Wnt signaling pathway / 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-M9N / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.41 Å
AuthorsZhao, Y. / Jones, E.Y.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MR/M000141/1 United Kingdom
Cancer Research UKC375/A17721 United Kingdom
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors.
Authors: Atkinson, B.N. / Steadman, D. / Mahy, W. / Zhao, Y. / Sipthorp, J. / Bayle, E.D. / Svensson, F. / Papageorgiou, G. / Jeganathan, F. / Frew, S. / Monaghan, A. / Bictash, M. / Jones, E.Y. / Fish, P.V.
History
DepositionOct 8, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.year
Revision 1.2Jul 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 1.3Jan 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 1.4Nov 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

Downloads & links

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Assembly

Deposited unit
A: Palmitoleoyl-protein carboxylesterase NOTUM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,70325
Polymers43,5671
Non-polymers2,13624
Water1,964109
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4390 Å2
ΔGint-35 kcal/mol
Surface area15940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.720, 71.890, 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
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 , 5 types, 132 molecules

#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-M9N / 2-[[(4~{S})-5-chloranyl-6-methyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-4-yl]sulfanyl]ethanoic acid


Mass: 278.779 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H11ClN2O2S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 109 / 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: 1.93 Å3/Da / Density % sol: 36.12 %
Crystal growTemperature: 300 K / Method: evaporation / pH: 4.2 / Details: 1.5M Ammonium sulfate 0.1 M Sodium citrate pH4.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9726 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 28, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9726 Å / Relative weight: 1
ReflectionResolution: 1.36→78.25 Å / Num. obs: 72713 / % possible obs: 99.6 % / Redundancy: 12.4 % / Biso Wilson estimate: 20.21 Å2 / CC1/2: 0.57 / Rmerge(I) obs: 0.087 / Net I/σ(I): 35.3
Reflection shellResolution: 1.36→1.38 Å / Num. unique obs: 3260 / CC1/2: 0.57

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Processing

Software
NameVersionClassification
PHENIXdev_2645refinement
xia2data scaling
PDB_EXTRACT3.25data extraction
DIALSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6R8P

6r8p


Resolution: 1.41→32.692 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 20.38
RfactorNum. reflection% reflection
Rfree0.1979 3348 5.11 %
Rwork0.1764 --
obs0.1775 65466 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 90.59 Å2 / Biso mean: 27.9502 Å2 / Biso min: 14.32 Å2
Refinement stepCycle: final / Resolution: 1.41→32.692 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2828 0 125 109 3062
Biso mean--47.42 31.34 -
Num. residues----354
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.013116
X-RAY DIFFRACTIONf_angle_d1.1344233
X-RAY DIFFRACTIONf_chiral_restr0.102439
X-RAY DIFFRACTIONf_plane_restr0.008539
X-RAY DIFFRACTIONf_dihedral_angle_d13.5321776
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.41-1.43020.3181180.29442565
1.4302-1.45150.28251360.26652574
1.4515-1.47420.29151520.26282522
1.4742-1.49830.2871280.2342592
1.4983-1.52420.27681500.23412512
1.5242-1.55190.22331220.20962576
1.5519-1.58170.24671360.20342586
1.5817-1.6140.21331260.19772560
1.614-1.64910.2231270.19042546
1.6491-1.68750.21951380.18782587
1.6875-1.72970.22241430.18422550
1.7297-1.77640.19611550.17032553
1.7764-1.82870.17041430.15542578
1.8287-1.88770.1931340.15872565
1.8877-1.95520.17791340.16042593
1.9552-2.03350.2161610.15872548
2.0335-2.1260.18691410.16292621
2.126-2.23810.18151350.16132578
2.2381-2.37820.19441540.16762589
2.3782-2.56180.19241310.17332604
2.5618-2.81950.21691380.17992632
2.8195-3.22720.21671410.17812639
3.2272-4.06470.17171420.16782673
4.0647-32.6920.18491630.17682775
Refinement TLS params.Method: refined / Origin x: 4.8046 Å / Origin y: -1.4878 Å / Origin z: -2.0527 Å
111213212223313233
T0.1324 Å2-0.0021 Å2-0.0013 Å2-0.1491 Å20.0185 Å2--0.1406 Å2
L0.7816 °20.0475 °2-0.0727 °2-1.0821 °20.0547 °2--0.716 °2
S-0.0186 Å °-0.0094 Å °0.0159 Å °0.0302 Å °0.0053 Å °0.0013 Å °-0.0428 Å °0.0045 Å °0.0125 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA87 - 827
2X-RAY DIFFRACTION1allB1

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