7LXT

Structure of Plasmodium falciparum 20S proteasome with bound bortezomib


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.40 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.1 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: 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 ...

    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; ltilley@unimelb.edu.au sandy.gould@takeda.com.



Macromolecules
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Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome alpha-1 subunitA, O260Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_0807500
EC: 3.4.25.1
UniProt
Find proteins for Q8IAR3 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 2
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome alpha-2 subunitB, P235Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_0608500
EC: 3.4.25.1
UniProt
Find proteins for C6KST3 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 3
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome alpha-3 subunitC, Q246Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_1353800
EC: 3.4.25.1
UniProt
Find proteins for Q8IDG3 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 4
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome alpha-4 subunitD, R241Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_1353900
EC: 3.4.25.1
UniProt
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Entity ID: 5
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome alpha-5 subunitE, S256Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_0727400
EC: 3.4.25.1
UniProt
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Entity ID: 6
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome alpha-6 subunitF, T254Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_1474800
EC: 3.4.25.1
UniProt
Find proteins for Q8IK90 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 7
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome alpha-7 subunitG, U252Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_0317000
EC: 3.4.25.1
UniProt
Find proteins for O77396 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 8
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome beta-1 subunitH, V252Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_0931800
EC: 3.4.25.1
UniProt
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Entity ID: 9
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome beta-2 subunitI, W229Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_1328100
EC: 3.4.25.1
UniProt
Find proteins for Q8I6T3 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 10
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome beta-3 subunitJ, X218Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_0108000
EC: 3.4.25.1
UniProt
Find proteins for Q8I261 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 11
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome beta-4 subunitK, Y195Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_1470900
EC: 3.4.25.1
UniProt
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Entity ID: 12
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome beta-5 subunitL, Z211Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_1011400
EC: 3.4.25.1
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Entity ID: 13
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome beta-6 subunitM,
AA [auth a]
240Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_0518300
EC: 3.4.25.1
UniProt
Find proteins for A0A5K1K7U1 (Plasmodium falciparum (isolate 3D7))
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Entity ID: 14
MoleculeChainsSequence LengthOrganismDetailsImage
20S proteasome beta-7 subunitN,
BA [auth b]
265Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF3D7_0803800
EC: 3.4.25.1
UniProt
Find proteins for Q7K6A9 (Plasmodium falciparum (isolate 3D7))
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Small Molecules
Ligands 1 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
BO2 (Subject of Investigation/LOI)
Query on BO2

Download Ideal Coordinates CCD File 
CA [auth H],
DA [auth I],
EA [auth L],
FA [auth V],
GA [auth W],
CA [auth H],
DA [auth I],
EA [auth L],
FA [auth V],
GA [auth W],
HA [auth Z]
N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE
C19 H25 B N4 O4
GXJABQQUPOEUTA-RDJZCZTQSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.40 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report




Entry History & Funding Information

Deposition Data


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

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