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- PDB-9yuy: Structure of the Plasmodium falciparum 20S proteasome in complex ... -

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Basic information

Entry
Database: PDB / ID: 9yuy
TitleStructure of the Plasmodium falciparum 20S proteasome in complex with a beta5-selective covalent syringolin analogue inhibitor.
Components
  • (Proteasome endopeptidase ...) x 3
  • (Proteasome subunit ...) x 11
KeywordsHYDROLASE / Proteasome / 20S / Inhibitor / Plasmodium / Covalent
Function / homology
Function and homology information


ER-Phagosome pathway / Cross-presentation of soluble exogenous antigens (endosomes) / Proteasome assembly / Antigen processing: Ub, ATP-independent proteasomal degradation / 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 ...ER-Phagosome pathway / Cross-presentation of soluble exogenous antigens (endosomes) / Proteasome assembly / Antigen processing: Ub, ATP-independent proteasomal degradation / 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 protein 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 / endopeptidase activity / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / hydrolase activity / nucleus / cytoplasm / cytosol
Similarity search - Function
Proteasome subunit alpha 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 subunit alpha 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
Similarity search - Domain/homology
: / 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 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 3D7 (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsYan, N.L. / Gu, X. / Fajtova, P. / Tse, E. / Melo, A. / Southworth, D.R. / O'Donoghue, A. / Sello, J.K. / Gestwicki, J.E.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J Med Chem / Year: 2026
Title: An Optimized Route to the Syringolin Natural Products Enables Combinatorial Synthesis of Selective, Bioactive Inhibitors of the 20S Proteasome.
Authors: Xilin Gu / Pavla Fajtova / Nicholas L Yan / Aditi Saxena / Fan Fei / Jiyun Zhu / Eric Tse / Arthur Melo / Euna Yoo / Nathan H Buchwald / Daniel R Southworth / Matthew Bogyo / Joseph L Derisi ...Authors: Xilin Gu / Pavla Fajtova / Nicholas L Yan / Aditi Saxena / Fan Fei / Jiyun Zhu / Eric Tse / Arthur Melo / Euna Yoo / Nathan H Buchwald / Daniel R Southworth / Matthew Bogyo / Joseph L Derisi / Jason E Gestwicki / Anthony J O'Donoghue / Jason K Sello /
Abstract: The syringolin natural products are covalent inhibitors of the 20S proteasome that inspire therapeutic development. Here, we report a new route to the syringolins amenable to solution and solid-phase ...The syringolin natural products are covalent inhibitors of the 20S proteasome that inspire therapeutic development. Here, we report a new route to the syringolins amenable to solution and solid-phase synthesis that overcomes a problematic macrocyclization. Exploiting our synthetic approach and substrate mimicry models for proteasome inhibition by the syringolins, we generated a collection of hypothetically selective inhibitors of the proteasome, which is an emerging target for antimalarial drugs. We identified compounds from the library having high second-order rate constants for proteasome inhibition and nanomolar antiparasitic activity. They exhibited selectivity for the proteasome over the human proteasome. We solved cryo-EM structures of an inhibitor bound to both 20S proteasomes, revealing key contacts favoring species-selective inhibition. Together, this work provides an improved route to syringolin analogs, sheds new light on substrate mimicry by the syringolins, and provides a structural basis for the pursuit of new antimalarial drugs.
History
DepositionOct 23, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Proteasome subunit alpha type
D: Proteasome subunit alpha type
E: Proteasome subunit alpha type
F: Proteasome endopeptidase complex
G: Proteasome subunit alpha type-3, putative
K: Proteasome subunit beta
L: Proteasome subunit beta
M: Proteasome subunit beta
Q: Proteasome subunit alpha type
R: Proteasome subunit alpha type
S: Proteasome subunit alpha type
T: Proteasome endopeptidase complex
U: Proteasome subunit alpha type-3, putative
Y: Proteasome subunit beta
Z: Proteasome subunit beta
a: Proteasome subunit beta
A: Proteasome endopeptidase complex
B: Proteasome endopeptidase complex
H: Proteasome subunit beta type-6, putative
I: Proteasome subunit beta
J: Proteasome subunit beta
N: Proteasome subunit beta
O: Proteasome endopeptidase complex
P: Proteasome endopeptidase complex
V: Proteasome subunit beta type-6, putative
W: Proteasome subunit beta
X: Proteasome subunit beta
b: Proteasome subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)794,94630
Polymers793,69528
Non-polymers1,2512
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Proteasome subunit ... , 11 types, 22 molecules CQDRESGUKYLZMaHVIWJXNb

#1: Protein Proteasome subunit alpha type


Mass: 27977.664 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_1353800 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8IDG3, proteasome endopeptidase complex
#2: Protein Proteasome subunit alpha type


Mass: 27263.285 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_1353900 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8IDG2, proteasome endopeptidase complex
#3: Protein Proteasome subunit alpha type


Mass: 28417.367 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0727400 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8IBI3, proteasome endopeptidase complex
#5: Protein Proteasome subunit alpha type-3, putative


Mass: 29324.295 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0317000 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O77396, proteasome endopeptidase complex
#6: Protein Proteasome subunit beta


Mass: 22889.105 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_1470900 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8IKC9, proteasome endopeptidase complex
#7: Protein Proteasome subunit beta


Mass: 30630.432 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_1011400 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8IJT1
#8: Protein Proteasome subunit beta


Mass: 27301.203 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0518300 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: A0A5K1K7U1, proteasome endopeptidase complex
#11: Protein Proteasome subunit beta type-6, putative


Mass: 32641.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0931800 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8I0U7, proteasome endopeptidase complex
#12: Protein Proteasome subunit beta


Mass: 29999.557 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_1328100 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8I6T3
#13: Protein Proteasome subunit beta


Mass: 24533.131 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0108000 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8I261, proteasome endopeptidase complex
#14: Protein Proteasome subunit beta


Mass: 30909.893 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0803800 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q7K6A9, proteasome endopeptidase complex

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Proteasome endopeptidase ... , 3 types, 6 molecules FTAOBP

#4: Protein Proteasome endopeptidase complex


Mass: 28871.697 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_1474800 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8IK90, proteasome endopeptidase complex
#9: Protein Proteasome endopeptidase complex


Mass: 29531.656 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0807500 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8IAR3, proteasome endopeptidase complex
#10: Protein Proteasome endopeptidase complex


Mass: 26556.391 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0608500 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: C6KST3, proteasome endopeptidase complex

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Non-polymers , 1 types, 2 molecules

#15: Chemical ChemComp-A1CY6 / methyl N-{[(2R)-1-({(5R,8R)-5-[(3-fluorophenyl)methyl]-2,7-dioxo-1,6-diazacyclododecan-8-yl}amino)-1-oxo-3-phenylpropan-2-yl]carbamoyl}-L-valinate


Mass: 625.731 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H44FN5O6 / 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 / Type: COMPLEX / Entity ID: #1-#6, #8-#13, #7, #14 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding 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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 46 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.1_5286model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36364 / Symmetry type: POINT
Atomic model buildingPDB-ID: 6MUW

6muw


Accession code: 6MUW / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.7 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00251076
ELECTRON MICROSCOPYf_angle_d0.45868968
ELECTRON MICROSCOPYf_dihedral_angle_d5.2726945
ELECTRON MICROSCOPYf_chiral_restr0.0427734
ELECTRON MICROSCOPYf_plane_restr0.0038788

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