[English] 日本語
Yorodumi
- PDB-7zyj: Leishmania tarentolae proteasome 20S subunit in complex with comp... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 7zyj
TitleLeishmania tarentolae proteasome 20S subunit in complex with compound 2
Components
  • (Proteasome alpha ...) x 3
  • (Proteasome subunit ...) x 10
  • Proteasome beta 6 subunit, putative
KeywordsHYDROLASE / proteasome. Cryo-EM / Inhibitor
Function / homology
Function and homology information


proteasome core complex / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / proteolysis involved in protein catabolic process / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / nucleus / cytoplasm
Similarity search - Function
Proteasome subunit alpha 1 / Aminohydrolase, N-terminal nucleophile (Ntn) domain / Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1 / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha5 / Proteasome subunit alpha6 / Proteasome beta-type subunits signature. / Peptidase T1A, proteasome beta-subunit ...Proteasome subunit alpha 1 / Aminohydrolase, N-terminal nucleophile (Ntn) domain / Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1 / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha5 / Proteasome subunit alpha6 / Proteasome beta-type subunits signature. / Peptidase T1A, proteasome beta-subunit / Proteasome beta-type subunit, conserved site / Proteasome subunit A N-terminal signature / Proteasome alpha-type subunits signature. / Proteasome alpha-subunit, N-terminal domain / Proteasome subunit A N-terminal signature Add an annotation / Proteasome B-type subunit / Proteasome beta-type subunit profile. / : / Proteasome alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome subunit / Proteasome, subunit alpha/beta / Nucleophile aminohydrolases, N-terminal / 4-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-KFC / Proteasome beta 6 subunit, putative / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit alpha type-5 / Proteasome subunit alpha type / Proteasome alpha 7 subunit, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta ...Chem-KFC / Proteasome beta 6 subunit, putative / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit alpha type-5 / Proteasome subunit alpha type / Proteasome alpha 7 subunit, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit alpha type-1
Similarity search - Component
Biological speciesLeishmania tarentolae (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsSrinivas, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: 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
DepositionMay 24, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Proteasome subunit alpha type
B: Proteasome subunit alpha type
C: Proteasome subunit alpha type
D: Proteasome subunit alpha type
E: Proteasome alpha 5 subunit, putative
F: Proteasome alpha 1 subunit, putative
G: Proteasome alpha 7 subunit, putative
H: Proteasome subunit beta
I: Proteasome subunit beta
J: Proteasome subunit beta
K: Proteasome subunit beta
L: Proteasome subunit beta
M: Proteasome beta 6 subunit, putative
N: Proteasome subunit beta
a: Proteasome subunit alpha type
b: Proteasome subunit alpha type
c: Proteasome subunit alpha type
d: Proteasome subunit alpha type
e: Proteasome alpha 5 subunit, putative
f: Proteasome alpha 1 subunit, putative
g: Proteasome alpha 7 subunit, putative
h: Proteasome subunit beta
i: Proteasome subunit beta
j: Proteasome subunit beta
k: Proteasome subunit beta
l: Proteasome subunit beta
m: Proteasome beta 6 subunit, putative
n: Proteasome subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)807,78430
Polymers807,09328
Non-polymers6912
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

-
Components

-
Proteasome subunit ... , 10 types, 20 molecules AaBbCcDdHhIiJjKkLlNn

#1: Protein Proteasome subunit alpha type


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 Proteasome subunit alpha type


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 Proteasome subunit alpha type


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 Proteasome subunit alpha type


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 Proteasome subunit beta


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 Proteasome subunit beta


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 Proteasome subunit beta


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 Proteasome subunit beta


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 Proteasome subunit beta


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 Proteasome subunit beta


Mass: 24580.037 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KSC5

-
Proteasome alpha ... , 3 types, 6 molecules EeFfGg

#5: Protein Proteasome alpha 5 subunit, putative


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 Proteasome alpha 1 subunit, putative


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 Proteasome alpha 7 subunit, putative


Mass: 25591.826 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Leishmania tarentolae (eukaryote) / References: UniProt: A0A640KJI7

-
Protein / Non-polymers , 2 types, 4 molecules Mm

#13: Protein Proteasome beta 6 subunit, putative


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 ChemComp-KFC / ~{N}-cyclopentyl-6-methyl-4-phenylazanyl-quinoline-2-carboxamide


Mass: 345.438 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H23N3O / Feature type: SUBJECT OF INVESTIGATION

-
Details

Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

-
Sample preparation

ComponentName: Proteasome / Type: COMPLEX / Entity ID: #1-#14 / Source: NATURAL
Molecular weightValue: 0.84 MDa / Experimental value: NO
Source (natural)Organism: Leishmania tarentolae (eukaryote)
Buffer solutionpH: 7
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

-
Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 20000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 1 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

-
Processing

EM softwareName: cisTEM / Version: 1 / Category: final Euler assignment
CTF correctionType: NONE
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 260000 / Symmetry type: POINT

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more