- EMDB-16963: Leishmania tarentolae proteasome 20S subunit in complex with 1-Be... -
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Basic information
Entry
Database: EMDB / ID: EMD-16963
Title
Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
Map data
Sample
Complex: Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
Protein or peptide: x 13 types
Protein or peptide: x 1 types
Ligand: x 1 types
Keywords
Proteasome 20S subunit / UNKNOWN FUNCTION
Function / homology
Function and homology information
proteasome core complex / proteasome core complex, beta-subunit complex / proteasomal protein catabolic process / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / 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 / proteasomal protein catabolic process / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteolysis involved in protein catabolic process / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / nucleus / cytoplasm / cytosol Similarity search - Function
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.
Entire : Leishmania tarentolae proteasome 20S subunit in complex with 1-Be...
Entire
Name: Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
Components
Complex: Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
Protein or peptide: Proteasome subunit alpha type
Protein or peptide: Proteasome subunit alpha type
Protein or peptide: Proteasome subunit alpha type
Protein or peptide: Proteasome subunit alpha type
Protein or peptide: Proteasome alpha 5 subunit, putative
Protein or peptide: Proteasome alpha 1 subunit, putative
Protein or peptide: Proteasome alpha 7 subunit, putative
Protein or peptide: Proteasome subunit beta
Protein or peptide: Proteasome subunit beta
Protein or peptide: Proteasome subunit beta
Protein or peptide: Proteasome subunit beta
Protein or peptide: Proteasome beta 6 subunit, putative
Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 94595
Initial angle assignment
Type: NOT APPLICABLE
Final angle assignment
Type: NOT APPLICABLE
FSC plot (resolution estimation)
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Atomic model buiding 1
Initial model
Chain - Source name: Other / Chain - Initial model type: experimental model / Details: Unpublished model
Refinement
Protocol: FLEXIBLE FIT
Output model
PDB-8olu: Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
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