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- PDB-7zyj: Leishmania tarentolae proteasome 20S subunit in complex with comp... -

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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 / 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
Proteasome subunit alpha 1 / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha6 / Proteasome subunit alpha5 / Proteasome beta-type subunits signature. / Peptidase T1A, proteasome beta-subunit / Proteasome beta-type subunit, conserved site / Proteasome subunit A N-terminal signature ...Proteasome subunit alpha 1 / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha6 / Proteasome subunit alpha5 / 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 alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome B-type subunit / Proteasome beta-type subunit profile. / Proteasome subunit / Proteasome, subunit alpha/beta / Nucleophile aminohydrolases, N-terminal
Similarity search - Domain/homology
Chem-KFC / Proteasome beta 6 subunit, putative / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome alpha 5 subunit, putative / 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 alpha 5 subunit, putative / 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 alpha 1 subunit, putative
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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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

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Components

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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

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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

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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

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Details

Has ligand of interestY

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Experimental details

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Experiment

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

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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

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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)

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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

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