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- PDB-6tcz: Leishmania tarentolae proteasome 20S subunit complexed with LXE408 -

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Basic information

Entry
Database: PDB / ID: 6tcz
TitleLeishmania tarentolae proteasome 20S subunit complexed with LXE408
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 / threonine-type endopeptidase activity / proteolysis involved in protein catabolic process / gluconeogenesis / proteasomal protein catabolic process / 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 / threonine-type endopeptidase activity / proteolysis involved in protein catabolic process / gluconeogenesis / proteasomal protein catabolic process / 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-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 ...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: 3.4 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

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Structure visualization

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  • Deposited structure unit
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  • Superimposition on EM map
  • EMDB-10462
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Structure viewerMolecule:
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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)848,73130
Polymers847,84528
Non-polymers8872
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area119650 Å2
ΔGint-446 kcal/mol
Surface area218850 Å2
MethodPISA

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Components

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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: 30280.010 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: 27603.570 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: 33704.867 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

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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

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Non-polymers , 1 types, 2 molecules

#15: 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 / 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: Leishmania tarentolae proteasome 20S subunit complex / Type: COMPLEX / Entity ID: #1-#14 / Source: RECOMBINANT
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

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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 FIELDBright-field microscopy
Image recordingElectron dose: 1 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: NONE
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 38000 / Symmetry type: POINT

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