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- PDB-6t2k: Furano[2,3-d]prymidine amides as Notum inhibitors -

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Basic information

Entry
Database: PDB / ID: 6t2k
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-M9K / Palmitoleoyl-protein carboxylesterase NOTUM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.38 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 13, 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)44,81812
Polymers43,5671
Non-polymers1,25111
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1860 Å2
ΔGint-43 kcal/mol
Surface area15420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.620, 72.130, 78.090
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
#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 , 4 types, 156 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-M9K / 2-(6-chloranyl-7-cyclopropyl-thieno[3,2-d]pyrimidin-4-yl)sulfanylethanoic acid


Mass: 300.784 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H9ClN2O2S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 36.17 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / 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: I24 / Wavelength: 0.9726 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: May 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9726 Å / Relative weight: 1
ReflectionResolution: 1.38→47.39 Å / Num. obs: 69891 / % possible obs: 100 % / Redundancy: 12.6 % / CC1/2: 0.5 / Rmerge(I) obs: 0.079 / Net I/σ(I): 14.1
Reflection shellResolution: 1.38→1.4 Å / Num. unique obs: 3429 / CC1/2: 0.5

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Processing

Software
NameVersionClassification
PHENIXdev_3488refinement
PDB_EXTRACT3.25data extraction
xia2data reduction
xia2data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6R8P

6r8p


Resolution: 1.38→47.388 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.92
RfactorNum. reflection% reflection
Rfree0.2142 3458 4.95 %
Rwork0.1876 --
obs0.1889 69815 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 118.46 Å2 / Biso mean: 29.5921 Å2 / Biso min: 14.38 Å2
Refinement stepCycle: final / Resolution: 1.38→47.388 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2758 0 73 146 2977
Biso mean--52.66 39.2 -
Num. residues----343
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.38-1.39890.32111430.30192611
1.3989-1.41890.33021350.3042645
1.4189-1.44010.30871370.28842603
1.4401-1.46260.30081350.2692596
1.4626-1.48660.32271180.25832661
1.4866-1.51220.24511500.23982601
1.5122-1.53970.24461380.22382612
1.5397-1.56930.23581640.21692598
1.5693-1.60140.2641480.21212623
1.6014-1.63620.27921440.20182628
1.6362-1.67430.22121360.2022638
1.6743-1.71610.24141420.19552633
1.7161-1.76250.25751460.18152635
1.7625-1.81440.2291410.18372622
1.8144-1.8730.25051270.1772663
1.873-1.93990.21481190.17342644
1.9399-2.01760.20091450.17222628
2.0176-2.10940.18911630.172647
2.1094-2.22060.21061360.1662677
2.2206-2.35970.20811280.16962672
2.3597-2.54190.21361240.17752690
2.5419-2.79770.18311430.1852688
2.7977-3.20240.20981220.18712724
3.2024-4.03440.19971340.17382736
4.0344-4.7380.20211400.19222882
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3667-0.062-0.06821.82750.47933.0493-0.029-0.02730.15780.08150.0218-0.0911-0.24980.08240.00160.1846-0.0082-0.01780.15970.01220.20118.99111.01932.5731
21.8072-0.0592-0.851.94990.54193.74640.11310.00290.18810.0388-0.0233-0.0595-0.3409-0.0406-0.07010.1428-0.0087-0.02990.08270.02110.14027.08187.3969-1.8526
31.88540.5799-1.21692.7647-1.4098.9876-0.02490.31210.4053-0.09480.0247-0.1044-0.8419-0.0815-0.01550.24950.0079-0.03210.19890.06970.24521.871914.6824-9.8867
41.9281-0.72760.75134.8009-2.6873.09540.00330.01740.050.06720.03060.2234-0.1468-0.082-0.10010.1187-0.00330.00810.1296-0.00910.1304-0.4535-1.0889-5.2761
54.0573.1220.64745.24474.01984.73520.1445-0.47410.13430.332-0.36450.4305-0.0028-0.30330.2070.1787-0.00580.04260.23650.01430.2373-10.4369-2.15624.6528
62.0338-0.4833-0.06722.4651-1.56222.7589-0.0581-0.1733-0.16660.17860.0205-0.0249-0.04780.04270.03830.1395-0.01490.00680.1332-0.01090.14332.8774-11.6978-0.3064
74.8055-4.28015.16254.7583-5.99338.85620.0226-0.285-0.3989-0.20750.03430.0360.479-0.062-0.06860.18220.00480.03540.1930.04230.25053.6029-23.16581.9817
82.3227-0.4698-0.73352.0107-1.53411.8168-0.02950.00030.00820.0137-0.0721-0.19950.05640.17930.15020.1710.00020.01330.18740.00110.204412.8675-11.237-8.0086
91.5459-0.39920.02253.1051-1.51832.22630.06640.1589-0.117-0.2777-0.0483-0.04120.19670.09210.04940.1741-0.01080.02340.1759-0.03020.18910.6929-13.8218-14.3547
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 88 through 159 )A88 - 159
2X-RAY DIFFRACTION2chain 'A' and (resid 160 through 203 )A160 - 203
3X-RAY DIFFRACTION3chain 'A' and (resid 204 through 224 )A204 - 224
4X-RAY DIFFRACTION4chain 'A' and (resid 225 through 286 )A225 - 286
5X-RAY DIFFRACTION5chain 'A' and (resid 287 through 320 )A287 - 320
6X-RAY DIFFRACTION6chain 'A' and (resid 321 through 357 )A321 - 357
7X-RAY DIFFRACTION7chain 'A' and (resid 358 through 375 )A358 - 375
8X-RAY DIFFRACTION8chain 'A' and (resid 376 through 406 )A376 - 406
9X-RAY DIFFRACTION9chain 'A' and (resid 407 through 451 )A407 - 451

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