7LXU

Structure of Plasmodium falciparum 20S proteasome with bound MPI-5


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.10 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome.

Xie, S.C.Metcalfe, R.D.Mizutani, H.Puhalovich, T.Hanssen, E.Morton, C.J.Du, Y.Dogovski, C.Huang, S.C.Ciavarri, J.Hales, P.Griffin, R.J.Cohen, L.H.Chuang, B.C.Wittlin, S.Deni, I.Yeo, T.Ward, K.E.Barry, D.C.Liu, B.Gillett, D.L.Crespo-Fernandez, B.F.Ottilie, S.Mittal, N.Churchyard, A.Ferguson, D.Aguiar, A.C.C.Guido, R.V.C.Baum, J.Hanson, K.K.Winzeler, E.A.Gamo, F.J.Fidock, D.A.Baud, D.Parker, M.W.Brand, S.Dick, L.R.Griffin, M.D.W.Gould, A.E.Tilley, L.

(2021) Proc Natl Acad Sci U S A 118

  • DOI: https://doi.org/10.1073/pnas.2107213118
  • Primary Citation of Related Structures:  
    7LXT, 7LXU, 7LXV

  • PubMed Abstract: 

    The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome ( Pf 20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax 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 P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf 20S than to human constitutive 20S ( Hs 20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf 20S and Hs 20Sc in complex with MPI-5 and Pf 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 P. falciparum , underpinning the design of potent and selective antimalarial proteasome inhibitors.


  • Organizational Affiliation

    Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome alpha-1 subunit
A, O
260Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome alpha-2 subunit
B, P
235Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for C6KST3 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome alpha-3 subunit
C, Q
246Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome alpha-4 subunit
D, R
241Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome alpha-5 subunit
E, S
256Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome alpha-6 subunit
F, T
254Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome alpha-7 subunit
G, U
252Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for O77396 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome beta-1 subunit
H, V
252Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome beta-2 subunit
I, W
229Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome beta-3 subunit
J, X
218Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for Q8I261 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome beta-4 subunit
K, Y
195Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome beta-5 subunit
L, Z
211Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 13
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome beta-6 subunitAA [auth a],
M
240Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 14
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome beta-7 subunitBA [auth b],
N
265Plasmodium falciparum 3D7Mutation(s): 0 
EC: 3.4.25.1
UniProt
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Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.10 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Australian Research Council (ARC)AustraliaFL150100106
Global Health Innovative Technology FundUnited StatesRFP-HTLP-H2019-101

Revision History  (Full details and data files)

  • Version 1.0: 2021-09-22
    Type: Initial release
  • Version 1.1: 2022-04-13
    Changes: Database references
  • Version 1.2: 2024-11-20
    Changes: Data collection, Structure summary