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Yorodumi- PDB-8olu: Leishmania tarentolae proteasome 20S subunit in complex with 1-Be... -
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-Basic information
Entry | Database: PDB / ID: 8olu | ||||||
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Title | Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide | ||||||
Components |
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Keywords | UNKNOWN FUNCTION / Proteasome 20S subunit | ||||||
Function / homology | Function and homology information proteasome core complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteasomal protein catabolic process / proteolysis involved in protein catabolic process / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / nucleus ...proteasome core complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteasomal protein catabolic process / proteolysis involved in protein catabolic process / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / nucleus / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Leishmania tarentolae (eukaryote) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.59 Å | ||||||
Authors | Rowland, P. | ||||||
Funding support | 1items
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Citation | Journal: J Med Chem / Year: 2023 Title: Structure-Guided Design and Synthesis of a Pyridazinone Series of Proteasome Inhibitors. Authors: Michael G Thomas / Kate McGonagle / Paul Rowland / David A Robinson / Peter G Dodd / Isabel Camino-Díaz / Lorna Campbell / Juan Cantizani / Pablo Castañeda / Daniel Conn / Peter D Craggs / ...Authors: Michael G Thomas / Kate McGonagle / Paul Rowland / David A Robinson / Peter G Dodd / Isabel Camino-Díaz / Lorna Campbell / Juan Cantizani / Pablo Castañeda / Daniel Conn / Peter D Craggs / Darren Edwards / Liam Ferguson / Andrew Fosberry / Laura Frame / Panchali Goswami / Xiao Hu / Justyna Korczynska / Lorna MacLean / Julio Martin / Nicole Mutter / Maria Osuna-Cabello / Christy Paterson / Imanol Peña / Erika G Pinto / Caterina Pont / Jennifer Riley / Yoko Shishikura / Frederick R C Simeons / Laste Stojanovski / John Thomas / Karolina Wrobel / Robert J Young / Filip Zmuda / Fabio Zuccotto / Kevin D Read / Ian H Gilbert / Maria Marco / Timothy J Miles / Pilar Manzano / Manu De Rycker / Abstract: There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, ...There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the proteasome. A related analogue, active against , showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8olu.cif.gz | 1.2 MB | Display | PDBx/mmCIF format |
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PDB format | pdb8olu.ent.gz | 980.4 KB | Display | PDB format |
PDBx/mmJSON format | 8olu.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8olu_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 8olu_full_validation.pdf.gz | 1.6 MB | Display | |
Data in XML | 8olu_validation.xml.gz | 168.5 KB | Display | |
Data in CIF | 8olu_validation.cif.gz | 261.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ol/8olu ftp://data.pdbj.org/pub/pdb/validation_reports/ol/8olu | HTTPS FTP |
-Related structure data
Related structure data | 16963MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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Noncrystallographic symmetry (NCS) | NCS domain:
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-Components
-Proteasome subunit ... , 10 types, 20 molecules AOBPCQDRHVIWJXKYLZNb
#1: Protein | Mass: 27178.107 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KZP5 #2: Protein | Mass: 25179.559 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KGL4 #3: Protein | Mass: 32321.438 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KBV2 #4: Protein | Mass: 27821.605 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KXA2 #8: Protein | Mass: 30280.010 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KBR2 #9: Protein | Mass: 27603.570 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KUX2 #10: Protein | Mass: 22470.887 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KQX8 #11: Protein | Mass: 23065.291 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KTY7 #12: Protein | Mass: 33576.738 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KW57 #14: Protein | Mass: 24737.232 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KSC5 |
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-Proteasome alpha ... , 3 types, 6 molecules ESFTGU
#5: Protein | Mass: 38312.316 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KG82 #6: Protein | Mass: 47978.633 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640L0A1 #7: Protein | Mass: 25591.826 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KJI7 |
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-Protein / Non-polymers , 2 types, 4 molecules Ma
#13: Protein | Mass: 37676.910 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640K9U9 #15: Chemical | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide Type: COMPLEX / Entity ID: #1-#11, #13-#14 / Source: NATURAL |
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Source (natural) | Organism: Leishmania tarentolae (eukaryote) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 3400 nm / Nominal defocus min: 1800 nm |
Image recording | Electron dose: 30 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 94595 / Symmetry type: POINT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Details: Unpublished model / Source name: Other / Type: experimental model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement | Resolution: 2.59→186.18 Å / Cor.coef. Fo:Fc: 0.895 / SU B: 6.111 / SU ML: 0.122 / ESU R: 0.235 Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 27.864 Å2
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Refinement step | Cycle: 1 / Total: 48930 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
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