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- PDB-7lxu: Structure of Plasmodium falciparum 20S proteasome with bound MPI-5 -

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Basic information

Entry
Database: PDB / ID: 7lxu
TitleStructure of Plasmodium falciparum 20S proteasome with bound MPI-5
Components
  • (20S proteasome alpha- ...) x 7
  • (20S proteasome beta- ...) x 7
KeywordsHYDROLASE / proteasome / plasmodium falciparum / malaria / drug / bortezomib
Function / homology
Function and homology information


Cross-presentation of soluble exogenous antigens (endosomes) / Proteasome assembly / Orc1 removal from chromatin / CDK-mediated phosphorylation and removal of Cdc6 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / KEAP1-NFE2L2 pathway / UCH proteinases / Ub-specific processing proteases / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation ...Cross-presentation of soluble exogenous antigens (endosomes) / Proteasome assembly / Orc1 removal from chromatin / CDK-mediated phosphorylation and removal of Cdc6 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / KEAP1-NFE2L2 pathway / UCH proteinases / Ub-specific processing proteases / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / MAPK6/MAPK4 signaling / ABC-family proteins mediated transport / AUF1 (hnRNP D0) binds and destabilizes mRNA / Neutrophil degranulation / proteasome core complex / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / ubiquitin-dependent protein catabolic process / endopeptidase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / hydrolase activity / nucleus / cytoplasm / cytosol
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-YHD / Proteasome subunit beta / Proteasome subunit alpha type-2 / Proteasome subunit alpha type-3, putative / Proteasome subunit beta / Proteasome subunit beta type-6, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type-6, putative / Proteasome subunit alpha type ...Chem-YHD / Proteasome subunit beta / Proteasome subunit alpha type-2 / Proteasome subunit alpha type-3, putative / Proteasome subunit beta / Proteasome subunit beta type-6, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type-6, putative / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit alpha type-1, putative / Proteasome subunit beta
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsMetcalfe, R.D. / Morton, C.J. / Xie, S.C. / Liu, B. / Hanssen, E. / Leis, A.P. / Tilley, L. / Griffin, M.D.W.
Funding support Australia, United States, 2items
OrganizationGrant numberCountry
Australian Research Council (ARC)FL150100106 Australia
Global Health Innovative Technology FundRFP-HTLP-H2019-101 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2021
Title: Design of proteasome inhibitors with oral efficacy in vivo against and selectivity over the human proteasome.
Authors: Stanley C Xie / Riley D Metcalfe / Hirotake Mizutani / Tanya Puhalovich / Eric Hanssen / Craig J Morton / Yawei Du / Con Dogovski / Shih-Chung Huang / Jeffrey Ciavarri / Paul Hales / Robert ...Authors: Stanley C Xie / Riley D Metcalfe / Hirotake Mizutani / Tanya Puhalovich / Eric Hanssen / Craig J Morton / Yawei Du / Con Dogovski / Shih-Chung Huang / Jeffrey Ciavarri / Paul Hales / Robert J Griffin / Lawrence H Cohen / Bei-Ching Chuang / Sergio Wittlin / Ioanna Deni / Tomas Yeo / Kurt E Ward / Daniel C Barry / Boyin Liu / David L Gillett / Benigno F Crespo-Fernandez / Sabine Ottilie / Nimisha Mittal / Alisje Churchyard / Daniel Ferguson / Anna Caroline C Aguiar / Rafael V C Guido / Jake Baum / Kirsten K Hanson / Elizabeth A Winzeler / Francisco-Javier Gamo / David A Fidock / Delphine Baud / Michael W Parker / Stephen Brand / Lawrence R Dick / Michael D W Griffin / Alexandra E Gould / Leann Tilley /
Abstract: The proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the 20S proteasome (20S) β5 active site and ...The proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the 20S proteasome (20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of compared with a human cell line and exhibit high potency against field isolates of and They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to 20S than to human constitutive 20S (20Sc). Comparison of the cryo-electron microscopy (EM) structures of 20S and 20Sc in complex with MPI-5 and 20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in , underpinning the design of potent and selective antimalarial proteasome inhibitors.
History
DepositionMar 5, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release
Revision 1.0Sep 22, 2021Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.0Sep 22, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Revision 1.1Apr 13, 2022Group: Database references / Category: citation / citation_author
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Revision 1.2Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3Jun 4, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
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Structure visualization

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Assembly

Deposited unit
A: 20S proteasome alpha-1 subunit
B: 20S proteasome alpha-2 subunit
C: 20S proteasome alpha-3 subunit
D: 20S proteasome alpha-4 subunit
E: 20S proteasome alpha-5 subunit
F: 20S proteasome alpha-6 subunit
G: 20S proteasome alpha-7 subunit
H: 20S proteasome beta-1 subunit
I: 20S proteasome beta-2 subunit
J: 20S proteasome beta-3 subunit
K: 20S proteasome beta-4 subunit
L: 20S proteasome beta-5 subunit
M: 20S proteasome beta-6 subunit
N: 20S proteasome beta-7 subunit
O: 20S proteasome alpha-1 subunit
P: 20S proteasome alpha-2 subunit
Q: 20S proteasome alpha-3 subunit
R: 20S proteasome alpha-4 subunit
S: 20S proteasome alpha-5 subunit
T: 20S proteasome alpha-6 subunit
U: 20S proteasome alpha-7 subunit
V: 20S proteasome beta-1 subunit
W: 20S proteasome beta-2 subunit
X: 20S proteasome beta-3 subunit
Y: 20S proteasome beta-4 subunit
Z: 20S proteasome beta-5 subunit
a: 20S proteasome beta-6 subunit
b: 20S proteasome beta-7 subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)763,59530
Polymers762,89028
Non-polymers7042
Water00
1


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

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Components

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20S proteasome alpha- ... , 7 types, 14 molecules AOBPCQDRESFTGU

#1: Protein 20S proteasome alpha-1 subunit


Mass: 29531.656 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8IAR3, proteasome endopeptidase complex
#2: Protein 20S proteasome alpha-2 subunit


Mass: 26556.391 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: C6KST3, proteasome endopeptidase complex
#3: Protein 20S proteasome alpha-3 subunit


Mass: 27977.664 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8IDG3, proteasome endopeptidase complex
#4: Protein 20S proteasome alpha-4 subunit


Mass: 27263.285 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8IDG2, proteasome endopeptidase complex
#5: Protein 20S proteasome alpha-5 subunit


Mass: 28417.367 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8IBI3, proteasome endopeptidase complex
#6: Protein 20S proteasome alpha-6 subunit


Mass: 28871.697 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8IK90, proteasome endopeptidase complex
#7: Protein 20S proteasome alpha-7 subunit


Mass: 29324.295 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: O77396, proteasome endopeptidase complex

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20S proteasome beta- ... , 7 types, 14 molecules HVIWJXKYLZMaNb

#8: Protein 20S proteasome beta-1 subunit


Mass: 29143.936 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8I0U7, proteasome endopeptidase complex
#9: Protein 20S proteasome beta-2 subunit


Mass: 25104.885 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8I6T3, proteasome endopeptidase complex
#10: Protein 20S proteasome beta-3 subunit


Mass: 24533.131 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8I261, proteasome endopeptidase complex
#11: Protein 20S proteasome beta-4 subunit


Mass: 22889.105 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8IKC9, proteasome endopeptidase complex
#12: Protein 20S proteasome beta-5 subunit


Mass: 23620.646 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q8IJT1, proteasome endopeptidase complex
#13: Protein 20S proteasome beta-6 subunit


Mass: 27301.203 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: A0A5K1K7U1, proteasome endopeptidase complex
#14: Protein 20S proteasome beta-7 subunit


Mass: 30909.893 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7
References: UniProt: Q7K6A9, proteasome endopeptidase complex

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Non-polymers , 1 types, 2 molecules

#15: Chemical ChemComp-YHD / N-[(1R)-2-([1,1'-biphenyl]-4-yl)-1-boronoethyl]-1-methyl-L-prolinamide


Mass: 352.235 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H25BN2O3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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 complexed with ML052
Type: COMPLEX / Entity ID: #1-#11, #13-#14 / Source: NATURAL
Molecular weightValue: 0.7 MDa / Experimental value: NO
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / C2 aperture diameter: 50 µm
Image recordingElectron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM software
IDNameVersionCategoryDetails
4RELION3CTF correctionwraper for motioncorr2, particle polishing
5MotionCorr22CTF correctionmotion correction
6cryoSPARC2.15CTF correctionparticle picking, 2D classes, 3D classes, refinements
10PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 38738 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00651714
ELECTRON MICROSCOPYf_angle_d0.6469842
ELECTRON MICROSCOPYf_dihedral_angle_d10.2316972
ELECTRON MICROSCOPYf_chiral_restr0.0467818
ELECTRON MICROSCOPYf_plane_restr0.0058908

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