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Basic information

Entry
Database: PDB / ID: 5fmg
TitleStructure and function based design of Plasmodium-selective proteasome inhibitors
Components
  • (PROTEASOME SUBUNIT ALPHA ...) x 4
  • (PROTEASOME SUBUNIT BETA ...) x 5
  • BETA3 PROTEASOME SUBUNIT, PUTATIVE
  • PROTEASOME COMPONENT C8, PUTATIVE
  • PROTEASOME SUBUNIT ALPHA, PUTATIVE
  • PROTEASOME, PUTATIVE
  • PROTEOSOME SUBUNIT ALPHA TYPE 1, PUTATIVEProteasome
KeywordsHYDROLASE / PROTEASOME / 20S / PLASMODIUM / MALARIA / INHIBITOR / DRUG DESIGN / CRYO-EM
Function / homology
Function and homology information


UCH proteinases / Ub-specific processing proteases / Neutrophil degranulation / Orc1 removal from chromatin / proteasome core complex, beta-subunit complex / proteasome core complex / proteasomal ubiquitin-independent protein catabolic process / proteasome endopeptidase complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity ...UCH proteinases / Ub-specific processing proteases / Neutrophil degranulation / Orc1 removal from chromatin / proteasome core complex, beta-subunit complex / proteasome core complex / proteasomal ubiquitin-independent protein catabolic process / proteasome endopeptidase complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteasomal protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / ubiquitin-dependent protein catabolic process / endopeptidase activity / nucleus / cytoplasm
Proteasome subunit beta 7 / Proteasome subunit beta 4 / Proteasome subunit beta Pre3 / Proteasome subunit alpha 3 / Proteasome alpha-type subunits signature. / Proteasome subunit beta 2 / Proteasome subunit beta 1 / Proteasome subunit alpha 1 / Proteasome subunit alpha2 / Proteasome subunit alpha6 ...Proteasome subunit beta 7 / Proteasome subunit beta 4 / Proteasome subunit beta Pre3 / Proteasome subunit alpha 3 / Proteasome alpha-type subunits signature. / Proteasome subunit beta 2 / Proteasome subunit beta 1 / Proteasome subunit alpha 1 / Proteasome subunit alpha2 / Proteasome subunit alpha6 / Proteasome subunit alpha5 / Proteasome beta 3 subunit / Nucleophile aminohydrolases, N-terminal / Proteasome B-type subunit / Proteasome alpha-type subunit / Proteasome beta-type subunit, conserved site / Proteasome subunit A N-terminal signature / Proteasome, subunit alpha/beta / Proteasome alpha-subunit, N-terminal domain / Peptidase T1A, proteasome beta-subunit / Proteasome beta-type subunits signature. / Proteasome alpha-type subunit profile. / Proteasome beta-type subunit profile. / Proteasome subunit
Proteasome endopeptidase complex / Proteasome endopeptidase complex / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta type-6, putative ...Proteasome endopeptidase complex / Proteasome endopeptidase complex / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta type-6, putative / Proteasome subunit alpha type-3, putative / Proteasome endopeptidase complex / Proteasome subunit beta / Proteasome subunit beta
Biological speciesPLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsLi, H. / O'Donoghue, A.J. / van der Linden, W.A. / Xie, S.C. / Yoo, E. / Foe, I.T. / Tilley, L. / Craik, C.S. / da Fonseca, P.C.A. / Bogyo, M.
CitationJournal: Nature / Year: 2016
Title: Structure- and function-based design of Plasmodium-selective proteasome inhibitors.
Authors: Hao Li / Anthony J O'Donoghue / Wouter A van der Linden / Stanley C Xie / Euna Yoo / Ian T Foe / Leann Tilley / Charles S Craik / Paula C A da Fonseca / Matthew Bogyo /
Abstract: The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially ...The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents.
Validation Report
SummaryFull reportAbout validation report
History
DepositionNov 4, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 2, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2017Group: Data collection / Category: em_software / Item: _em_software.image_processing_id

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Structure visualization

Movie
  • Deposited structure unit
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  • Superimposition on EM map
  • EMDB-3231
  • Imaged by UCSF Chimera
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  • EMDB-3231
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Structure viewerMolecule:
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Assembly

Deposited unit
A: PROTEASOME SUBUNIT ALPHA, PUTATIVE
B: PROTEASOME SUBUNIT ALPHA TYPE 2, PUTATIVE
C: PROTEASOME SUBUNIT ALPHA TYPE
D: PROTEASOME SUBUNIT ALPHA TYPE
E: PROTEASOME SUBUNIT ALPHA TYPE
F: PROTEOSOME SUBUNIT ALPHA TYPE 1, PUTATIVE
G: PROTEASOME COMPONENT C8, PUTATIVE
H: PROTEASOME, PUTATIVE
I: PROTEASOME SUBUNIT BETA TYPE
J: BETA3 PROTEASOME SUBUNIT, PUTATIVE
K: PROTEASOME SUBUNIT BETA TYPE
L: PROTEASOME SUBUNIT BETA TYPE
M: PROTEASOME SUBUNIT BETA TYPE
N: PROTEASOME SUBUNIT BETA TYPE
O: PROTEASOME SUBUNIT ALPHA, PUTATIVE
P: PROTEASOME SUBUNIT ALPHA TYPE 2, PUTATIVE
Q: PROTEASOME SUBUNIT ALPHA TYPE
R: PROTEASOME SUBUNIT ALPHA TYPE
S: PROTEASOME SUBUNIT ALPHA TYPE
T: PROTEOSOME SUBUNIT ALPHA TYPE 1, PUTATIVE
U: PROTEASOME COMPONENT C8, PUTATIVE
V: PROTEASOME, PUTATIVE
W: PROTEASOME SUBUNIT BETA TYPE
X: BETA3 PROTEASOME SUBUNIT, PUTATIVE
Y: PROTEASOME SUBUNIT BETA TYPE
Z: PROTEASOME SUBUNIT BETA TYPE
a: PROTEASOME SUBUNIT BETA TYPE
b: PROTEASOME SUBUNIT BETA TYPE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)764,27230
Polymers762,89028
Non-polymers1,3822
Water0
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA

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Components

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Protein/peptide , 5 types, 10 molecules AOFTGUHVJX

#1: Protein/peptide PROTEASOME SUBUNIT ALPHA, PUTATIVE /


Mass: 29531.656 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8IAR3, proteasome endopeptidase complex
#6: Protein/peptide PROTEOSOME SUBUNIT ALPHA TYPE 1, PUTATIVE / Proteasome


Mass: 28871.697 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8IK90
#7: Protein/peptide PROTEASOME COMPONENT C8, PUTATIVE /


Mass: 29324.295 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: O77396
#8: Protein/peptide PROTEASOME, PUTATIVE /


Mass: 29143.936 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8I0U7, proteasome endopeptidase complex
#10: Protein/peptide BETA3 PROTEASOME SUBUNIT, PUTATIVE


Mass: 24533.131 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8I261, proteasome endopeptidase complex

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PROTEASOME SUBUNIT ALPHA ... , 4 types, 8 molecules BPCQDRES

#2: Protein/peptide PROTEASOME SUBUNIT ALPHA TYPE 2, PUTATIVE /


Mass: 26556.391 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: C6KST3, proteasome endopeptidase complex
#3: Protein/peptide PROTEASOME SUBUNIT ALPHA TYPE /


Mass: 27977.664 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8IDG3, proteasome endopeptidase complex
#4: Protein/peptide PROTEASOME SUBUNIT ALPHA TYPE /


Mass: 27263.285 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8IDG2, proteasome endopeptidase complex
#5: Protein/peptide PROTEASOME SUBUNIT ALPHA TYPE /


Mass: 28417.367 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8IBI3, proteasome endopeptidase complex

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PROTEASOME SUBUNIT BETA ... , 5 types, 10 molecules IWKYLZMaNb

#9: Protein/peptide PROTEASOME SUBUNIT BETA TYPE /


Mass: 25104.885 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8I6T3, proteasome endopeptidase complex
#11: Protein/peptide PROTEASOME SUBUNIT BETA TYPE /


Mass: 22889.105 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8IKC9, proteasome endopeptidase complex
#12: Protein/peptide PROTEASOME SUBUNIT BETA TYPE /


Mass: 23620.646 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q8IJT1, proteasome endopeptidase complex
#13: Protein/peptide PROTEASOME SUBUNIT BETA TYPE /


Mass: 27301.203 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: C0H4E8, proteasome endopeptidase complex
#14: Protein/peptide PROTEASOME SUBUNIT BETA TYPE /


Mass: 30909.893 Da / Num. of mol.: 2
Details: THE SAMPLE PROTEIN COMPONENTS ARE DEPOSITED IN THE PLASMODB (THE PLASMODIUM GENOME RESOURCE)
Source method: isolated from a natural source
Source: (natural) PLASMODIUM FALCIPARUM (malaria parasite P. falciparum)
References: UniProt: Q7K6A9, proteasome endopeptidase complex

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Non-polymers , 1 types, 2 molecules

#15: Chemical ChemComp-7F1 / (2S)-N-[(E,2S)-1-(1H-indol-3-yl)-4-methylsulfonyl-but-3-en-2-yl]-2-[[(2S)-3-(1H-indol-3-yl)-2-(2-morpholin-4-ylethanoylamino)propanoyl]amino]-4-methyl-pentanamide


Mass: 690.852 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H46N6O6S

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Details

Sequence details5FMG A PLASMODB PF3D7_0807500 5FMG O PLASMODB PF3D7_0807500 5FMG B PLASMODB PF3D7_0608500 5FMG P ...5FMG A PLASMODB PF3D7_0807500 5FMG O PLASMODB PF3D7_0807500 5FMG B PLASMODB PF3D7_0608500 5FMG P PLASMODB PF3D7_0608500 5FMG C PLASMODB PF3D7_1353800 5FMG Q PLASMODB PF3D7_1353800 5FMG D PLASMODB PF3D7_1353900 5FMG R PLASMODB PF3D7_1353900 5FMG E PLASMODB PF3D7_0727400 5FMG S PLASMODB PF3D7_0727400 5FMG F PLASMODB PF3D7_1474800 5FMG T PLASMODB PF3D7_1474800 5FMG G PLASMODB PF3D7_0317000 5FMG U PLASMODB PF3D7_0317000 5FMG H PLASMODB PF3D7_0931800 5FMG V PLASMODB PF3D7_0931800 5FMG I PLASMODB PF3D7_1328100 5FMG W PLASMODB PF3D7_1328100 5FMG J PLASMODB PF3D7_0108000 5FMG X PLASMODB PF3D7_0108000 5FMG K PLASMODB PF3D7_1470900 5FMG Y PLASMODB PF3D7_1470900 5FMG L PLASMODB PF3D7_1011400 5FMG Z PLASMODB PF3D7_1011400 5FMG M PLASMODB PF3D7_0518300 5FMG A PLASMODB PF3D7_0518300 5FMG N PLASMODB PF3D7_0803800 5FMG B PLASMODB PF3D7_0803800

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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: PLASMODIUM FALCIPARUM 20S PROTEASOME CORE BOUND TO A SPECIFIC INHIBITOR
Type: COMPLEX
Buffer solutionName: 50MM TRIS HCL, 5MM MGCL2, 1MM DITHIOTREITOL / pH: 7.5 / Details: 50MM TRIS HCL, 5MM MGCL2, 1MM DITHIOTREITOL
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: OTHER
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE
Details: VITRIFICATION 1 -- CRYOGEN- ETHANE, HUMIDITY- 95, INSTRUMENT- FEI VITROBOT MARK III, METHOD- BLOT 2.5 SECONDS BEFORE PLUNGING,

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS / Date: Sep 3, 2014
Details: EACH EXPOSURE WAS RECORDED AS 17 INDIVIDUAL FRAMES CAPTURED AT A RATE OF 0.056 SECOND PER FRAME, EACH WITH AN ELECTRON DOSE OF 2.8 ELECTRONS PER SQUARE ANGSTROM. DATA-SET RECORDED USING EPU SOFTWARE.
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 75000 X / Nominal defocus max: 3200 nm / Nominal defocus min: 1600 nm
Image recordingElectron dose: 4.8 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k)
Image scansNum. digital images: 1816

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Processing

EM software
IDNameCategory
1IMAGIC3D reconstruction
2SPIDER3D reconstruction
3TIGRIS3D reconstruction
CTF correctionDetails: FULL RECORDED IMAGE
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionMethod: PROJECTION MATCHING / Resolution: 3.6 Å / Num. of particles: 97720 / Nominal pixel size: 1.04 Å / Actual pixel size: 1.04 Å
Details: DISORDERED REGIONS WERE NOT MODELED SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-3231. (DEPOSITION ID: 14006).
Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL / Details: METHOD--FLEXIBLE
Atomic model buildingPDB-ID: 1IRU
RefinementHighest resolution: 3.6 Å
Refinement stepCycle: LAST / Highest resolution: 3.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms39236 0 98 0 39334

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