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- PDB-9jal: Cryo-EM structure of MPXV core protease in complex with compound A1 -

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Basic information

Entry
Database: PDB / ID: 9jal
TitleCryo-EM structure of MPXV core protease in complex with compound A1
Components
  • A1ECM-DI8-ALA-ETA
  • Core protease I7
KeywordsVIRAL PROTEIN / Orthopoxviruses / mpox / Protease / Viral replication / Drug discovery / inhibitor
Function / homologyPeptidase C57, Vaccinia virus protein I7 / Vaccinia virus I7 processing peptidase / cysteine-type peptidase activity / Papain-like cysteine peptidase superfamily / virion component / proteolysis / MPXVgp068
Function and homology information
Biological speciesMonkeypox virus
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsGao, Y. / Xie, X. / Lan, W. / Wang, W. / Yang, H.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82130105 China
National Natural Science Foundation of China (NSFC)81902063 China
CitationJournal: Nature / Year: 2025
Title: Substrate recognition and cleavage mechanism of the monkeypox virus core protease.
Authors: Yan Gao / Xiong Xie / Xiaoyu Zhang / Junyuan Cao / Weiqi Lan / Tian You / Dongxu Li / Xuxue Dong / Wenhao Dai / Yingchun Xiang / Shulei Hu / Weijuan Shang / Botao Wu / Yumin Zhang / Jin Xu / ...Authors: Yan Gao / Xiong Xie / Xiaoyu Zhang / Junyuan Cao / Weiqi Lan / Tian You / Dongxu Li / Xuxue Dong / Wenhao Dai / Yingchun Xiang / Shulei Hu / Weijuan Shang / Botao Wu / Yumin Zhang / Jin Xu / Xiaoce Liu / Haofeng Wang / Wanlong Hu / Mingjing Zhang / Yinkai Duan / Wen Cui / Hao Zhou / Shengjiang Mao / Handi Jia / Zhanqi Sun / Menghan Jia / Yue Yin / Henry C Nguyen / Kailin Yang / Bei Yang / Xiuna Yang / Xiaoyun Ji / Gengfu Xiao / Wei Wang / Leike Zhang / Zihe Rao / Hong Liu / Haitao Yang /
Abstract: Poxviruses cause severe diseases, including smallpox and mpox, that pose major threats to human health. The poxvirus core protease (Core) is essential for viral maturation and is highly conserved in ...Poxviruses cause severe diseases, including smallpox and mpox, that pose major threats to human health. The poxvirus core protease (Core) is essential for viral maturation and is highly conserved in poxviruses, making it an attractive antiviral target. However, the structure of Core remains unknown, hampering antiviral development. Here we determined the apo structure of monkeypox virus (MPXV) Core and the structure of Core in a complex with the inhibitor aloxistatin, a drug candidate for muscular dystrophy. These structures show that Core forms a homodimer that features a unique 'dancing couple' fold. The catalytic intermediate state of Core was characterized by an aldehyde derivative from a natural substrate (I-G18). This derivative binds covalently to the catalytic Cys328, shifting the active site of the viral protease from a closed conformation in the apo form to a favourable open conformation upon substrate binding. On the basis of the Core-I-G18 complex, we designed a series of peptidomimetic inhibitors with a nitrile warhead, which could covalently anchor with the catalytic Cys328. These compounds inhibit Core with half-maximal inhibitory concentrations of 44.9-100.3 nM, and exhibit potent and broad anti-poxvirus activity. Our studies provide a basis for designing wide-spectrum inhibitors against poxvirus infections.
History
DepositionAug 25, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 25, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Core protease I7
B: Core protease I7
C: A1ECM-DI8-ALA-ETA
D: A1ECM-DI8-ALA-ETA


Theoretical massNumber of molelcules
Total (without water)99,1424
Polymers99,1424
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Core protease I7 / I7L / MPXV-COP-062 / MPXV-SL-062 / MPXV-WRAIR062 / MPXVgp068 / Viral core cysteine proteinase / ...I7L / MPXV-COP-062 / MPXV-SL-062 / MPXV-WRAIR062 / MPXVgp068 / Viral core cysteine proteinase / Virion core cysteine protease


Mass: 49088.477 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Monkeypox virus
Gene: I7L, MPXV-CAM1990_02-060, MPXV-COP-062, MPXV-GAB1988_001-061, MPXV-Ikubi-060, MPXV-M2940_FCT-066, MPXV-M2957_Lagos-066, MPXV-M3021_Delta-066, MPXV-M5320_M15_Bayelsa-059, MPXV-Nig_SEV71_2_82- ...Gene: I7L, MPXV-CAM1990_02-060, MPXV-COP-062, MPXV-GAB1988_001-061, MPXV-Ikubi-060, MPXV-M2940_FCT-066, MPXV-M2957_Lagos-066, MPXV-M3021_Delta-066, MPXV-M5320_M15_Bayelsa-059, MPXV-Nig_SEV71_2_82-061, MPXV-PCH-063, MPXV-Singapore-066, MPXV-SL-062, MPXV-UK_P1-066, MPXV-UK_P2-066, MPXV-UK_P3-066, MPXV-UTC-057, MPXV-W_Nigeria-061, MPXV-WRAIR062, MPXV297957_057, MPXV298464_048, MPXV_DRC_Yandongi_069, MPXV_LIB1970_184_073, MPXV_RCG2003_358_073, MPXV_SUD2005_01_069, MPXV_ZAI1979_005_073, MPXVgp068, PDLMKLCO_00071
Production host: Escherichia coli (E. coli)
References: UniProt: Q5IXV7, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein/peptide A1ECM-DI8-ALA-ETA


Mass: 482.593 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
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: Protease Dimer / Type: COMPLEX / Details: Protease Dimer in complex with A1 / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Monkeypox virus
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
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: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 717581 / Algorithm: FOURIER SPACE / Symmetry type: POINT

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