[English] 日本語
Yorodumi
- PDB-6td5: Leishmania tarentolae proteasome 20S subunit complexed with LXE40... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 6td5
TitleLeishmania tarentolae proteasome 20S subunit complexed with LXE408 and bortezomib
Components
  • (Proteasome endopeptidase ...) x 2
  • (Proteasome subunit ...) x 12
KeywordsHYDROLASE / Proteasome complex / inhibitor / peptidase
Function / homology
Function and homology information


phosphoenolpyruvate carboxykinase activity / proteasome core complex / proteasome endopeptidase 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 / gluconeogenesis / ubiquitin-dependent protein catabolic process ...phosphoenolpyruvate carboxykinase activity / proteasome core complex / proteasome endopeptidase 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 / gluconeogenesis / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / hydrolase activity / protein kinase activity / protein phosphorylation / ATP binding / nucleus / cytoplasm
Similarity search - Function
Proteasome subunit alpha 3 / Proteasome subunit beta Pre3 / Proteasome subunit alpha2 / Proteasome subunit alpha4 / Proteasome subunit beta 1 / Phosphoenolpyruvate carboxykinase, N-terminal / Proteasome subunit alpha 1 / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit ...Proteasome subunit alpha 3 / Proteasome subunit beta Pre3 / Proteasome subunit alpha2 / Proteasome subunit alpha4 / Proteasome subunit beta 1 / Phosphoenolpyruvate carboxykinase, N-terminal / 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 / Ankyrin repeat-containing domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-BO2 / Chem-N2E / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome alpha 7 subunit, putative / Proteasome subunit beta / Proteasome subunit beta ...Chem-BO2 / Chem-N2E / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome alpha 7 subunit, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit family protein / Proteasome subunit alpha type / Proteasome subunit family protein / Proteasome subunit alpha type / Proteasome subunit alpha type
Similarity search - Component
Biological speciesLeishmania donovani (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsSrinivas, H.
CitationJournal: J Med Chem / Year: 2020
Title: Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.
Authors: Advait Nagle / Agnes Biggart / Celine Be / Honnappa Srinivas / Andreas Hein / Diana Caridha / Richard J Sciotti / Brandon Pybus / Mara Kreishman-Deitrick / Badry Bursulaya / Yin H Lai / Mu- ...Authors: Advait Nagle / Agnes Biggart / Celine Be / Honnappa Srinivas / Andreas Hein / Diana Caridha / Richard J Sciotti / Brandon Pybus / Mara Kreishman-Deitrick / Badry Bursulaya / Yin H Lai / Mu-Yun Gao / Fang Liang / Casey J N Mathison / Xiaodong Liu / Vince Yeh / Jeffrey Smith / Isabelle Lerario / Yongping Xie / Donatella Chianelli / Michael Gibney / Ashley Berman / Yen-Liang Chen / Jan Jiricek / Lauren C Davis / Xianzhong Liu / Jaime Ballard / Shilpi Khare / Fabian Kurt Eggimann / Alexandre Luneau / Todd Groessl / Michael Shapiro / Wendy Richmond / Kevin Johnson / Patrick J Rudewicz / Srinivasa P S Rao / Christopher Thompson / Tove Tuntland / Glen Spraggon / Richard J Glynne / Frantisek Supek / Christian Wiesmann / Valentina Molteni /
Abstract: Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we ...Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.
History
DepositionNov 7, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 26, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 2, 2020Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 21, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

-
Structure visualization

Movie
  • Deposited structure unit
  • Imaged by Jmol
  • Download
  • Superimposition on EM map
  • EMDB-10463
  • Imaged by UCSF Chimera
  • Download
Movie viewer
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 endopeptidase complex
E: Proteasome subunit alpha type
F: Proteasome subunit alpha type
G: Proteasome endopeptidase complex
H: Proteasome subunit beta
I: Proteasome subunit beta
J: Proteasome subunit beta
K: Proteasome subunit family protein
L: Proteasome subunit beta
M: Proteasome subunit beta
N: Proteasome subunit beta
a: Proteasome subunit alpha type
b: Proteasome subunit alpha type
c: Proteasome subunit alpha type
d: Proteasome endopeptidase complex
e: Proteasome subunit alpha type
f: Proteasome subunit alpha type
g: Proteasome endopeptidase complex
h: Proteasome subunit beta
i: Proteasome subunit beta
j: Proteasome subunit beta
k: Proteasome subunit family protein
l: Proteasome subunit beta
m: Proteasome subunit beta
n: Proteasome subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)810,59936
Polymers807,40728
Non-polymers3,1928
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area127000 Å2
ΔGint-403 kcal/mol
Surface area220250 Å2
MethodPISA

-
Components

-
Proteasome subunit ... , 12 types, 24 molecules AaBbCcEeFfHhIiJjKkLlMmNn

#1: Protein Proteasome subunit alpha type


Mass: 27178.107 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: Pa, CGC20_14335, CGC21_7870, LdCL_350054100 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: Q9UAB4*PLUS, proteasome endopeptidase complex
#2: Protein Proteasome subunit alpha type


Mass: 25179.559 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC20_21935, CGC21_34645, LdCL_210026400 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A3Q8IB07*PLUS, proteasome endopeptidase complex
#3: Protein Proteasome subunit alpha type


Mass: 32321.438 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC21_4565, LdCL_140008100 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A504Y5E1*PLUS, proteasome endopeptidase complex
#5: Protein Proteasome subunit alpha type


Mass: 38312.316 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC20_21875, CGC21_34705, LdCL_210027700 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A3Q8IC41*PLUS, proteasome endopeptidase complex
#6: Protein Proteasome subunit alpha type


Mass: 47978.633 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC20_29090, CGC21_13150 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A504XQ80*PLUS, proteasome endopeptidase complex
#8: Protein Proteasome subunit beta


Mass: 24426.352 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC20_24015, CGC21_10040 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A504X6A3*PLUS, proteasome endopeptidase complex
#9: Protein Proteasome subunit beta


Mass: 24377.994 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC20_14810, CGC21_7390, LdCL_350043900 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A3Q8IVH0*PLUS, proteasome endopeptidase complex
#10: Protein Proteasome subunit beta


Mass: 22470.887 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC20_14015, CGC21_21605, LdCL_280006000 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A3S7X127*PLUS, proteasome endopeptidase complex
#11: Protein Proteasome subunit family protein


Mass: 23065.291 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC21_12505 / Production host: Leishmania tarentolae (eukaryote) / References: UniProt: A0A504XH29*PLUS
#12: Protein Proteasome subunit beta


Mass: 22565.420 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC20_29060, CGC21_13180, LdCL_360022800 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A3Q8IIY4*PLUS, proteasome endopeptidase complex
#13: Protein Proteasome subunit beta


Mass: 37676.910 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC20_20280, CGC21_24485, LdCL_060006300 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A3S7WPD8*PLUS, proteasome endopeptidase complex
#14: Protein Proteasome subunit beta


Mass: 24737.232 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote)
Gene: CGC21_27345, CGC21_27360, LdCL_340051000, LdCL_340051300
Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A3Q8IIL6*PLUS, proteasome endopeptidase complex

-
Proteasome endopeptidase ... , 2 types, 4 molecules DdGg

#4: Protein Proteasome endopeptidase complex


Mass: 27821.605 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC21_1080 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A504XWY9*PLUS, proteasome endopeptidase complex
#7: Protein Proteasome endopeptidase complex


Mass: 25591.826 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania donovani (eukaryote) / Gene: CGC20_1425, CGC20_33255, CGC21_31345, LdCL_270006800 / Production host: Leishmania tarentolae (eukaryote)
References: UniProt: A0A3S5H7H2*PLUS, proteasome endopeptidase complex

-
Non-polymers , 2 types, 8 molecules

#15: Chemical
ChemComp-BO2 / N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE / BORTEZOMIB


Mass: 384.237 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C19H25BN4O4 / Comment: medication, anticancer*YM
#16: Chemical ChemComp-N2E / ~{N}-[4-fluoranyl-3-[6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]phenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide


Mass: 443.433 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H18FN7O2

-
Details

Has ligand of interestY

-
Experimental details

-
Experiment

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

-
Sample preparation

ComponentName: Leishmania tarentolae proteasome 20S subunit complexed with LXE408 and bortezomib
Type: COMPLEX / Entity ID: #1-#14 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Leishmania donovani (eukaryote)
Source (recombinant)Organism: Leishmania tarentolae (eukaryote)
Buffer solutionpH: 7.5
SpecimenConc.: 3 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
Image recordingElectron dose: 1 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

-
Processing

CTF correctionType: NONE
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 127000 / 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://pdbjlvh1.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