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Yorodumi- PDB-7zyj: Leishmania tarentolae proteasome 20S subunit in complex with comp... -
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-Basic information
Entry | Database: PDB / ID: 7zyj | ||||||
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Title | Leishmania tarentolae proteasome 20S subunit in complex with compound 2 | ||||||
Components |
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Keywords | HYDROLASE / proteasome. Cryo-EM / Inhibitor | ||||||
Function / homology | Function and homology information proteasome core complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / threonine-type endopeptidase activity / proteolysis involved in protein catabolic process / endopeptidase activity / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / nucleus ...proteasome core complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / threonine-type endopeptidase activity / proteolysis involved in protein catabolic process / endopeptidase activity / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / nucleus / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Leishmania tarentolae (eukaryote) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å | ||||||
Authors | Srinivas, H. | ||||||
Funding support | 1items
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Citation | Journal: J Med Chem / Year: 2022 Title: Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT). Authors: Dennis C Koester / Vanessa M Marx / Sarah Williams / Jan Jiricek / Maxime Dauphinais / Olivier René / Sarah L Miller / Lei Zhang / Debjani Patra / Yen-Liang Chen / Harry Cheung / Jonathan ...Authors: Dennis C Koester / Vanessa M Marx / Sarah Williams / Jan Jiricek / Maxime Dauphinais / Olivier René / Sarah L Miller / Lei Zhang / Debjani Patra / Yen-Liang Chen / Harry Cheung / Jonathan Gable / Suresh B Lakshminarayana / Colin Osborne / Jean-Rene Galarneau / Upendra Kulkarni / Wendy Richmond / Angela Bretz / Linda Xiao / Frantisek Supek / Christian Wiesmann / Srinivas Honnappa / Celine Be / Pascal Mäser / Marcel Kaiser / Ryan Ritchie / Michael P Barrett / Thierry T Diagana / Christopher Sarko / Srinivasa P S Rao / Abstract: Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo- ...Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an model to predict the brain-to-plasma partition coefficient as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios () to cure a CNS disease such as HAT. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7zyj.cif.gz | 1.1 MB | Display | PDBx/mmCIF format |
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PDB format | pdb7zyj.ent.gz | 884.4 KB | Display | PDB format |
PDBx/mmJSON format | 7zyj.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7zyj_validation.pdf.gz | 1.7 MB | Display | wwPDB validaton report |
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Full document | 7zyj_full_validation.pdf.gz | 1.7 MB | Display | |
Data in XML | 7zyj_validation.xml.gz | 145.9 KB | Display | |
Data in CIF | 7zyj_validation.cif.gz | 231.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zy/7zyj ftp://data.pdbj.org/pub/pdb/validation_reports/zy/7zyj | HTTPS FTP |
-Related structure data
Related structure data | 15025MC 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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1 |
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-Components
-Proteasome subunit ... , 10 types, 20 molecules AaBbCcDdHhIiJjKkLlNn
#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: 24426.352 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KBR2 #9: Protein | Mass: 24377.994 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: 22565.420 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KW57 #14: Protein | Mass: 24580.037 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 EeFfGg
#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 Mm
#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: Proteasome / Type: COMPLEX / Entity ID: #1-#14 / Source: NATURAL |
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Molecular weight | Value: 0.84 MDa / Experimental value: NO |
Source (natural) | Organism: Leishmania tarentolae (eukaryote) |
Buffer solution | pH: 7 |
Specimen | Conc.: 2 mg/ml / 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: 20000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 1 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
-Processing
EM software | Name: cisTEM / Version: 1 / Category: final Euler assignment |
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CTF correction | Type: NONE |
3D reconstruction | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 260000 / Symmetry type: POINT |