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- EMDB-61294: Cryo-EM structure of MPXV protease in complex with compound A4 -

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Basic information

Entry
Database: EMDB / ID: EMD-61294
TitleCryo-EM structure of MPXV protease in complex with compound A4
Map data
Sample
  • Complex: Protease Dimer
    • Protein or peptide: Core protease I7
    • Protein or peptide: A1ECL-DI8-ALA-AEM
KeywordsOrthopoxviruses / mpox / Protease / Viral replication / Drug discovery / inhibitor / VIRAL PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.93 Å
AuthorsGao Y / Xie X / Lan W / Wang W / Yang H
Funding support China, 2 items
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, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateJun 25, 2025-
Current statusJun 25, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61294.png

Downloads & links

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Map

FileDownload / File: emd_61294.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 280 pix.
= 232.96 Å		0.83 Å/pix.
x 280 pix.
= 232.96 Å		0.83 Å/pix.
x 280 pix.
= 232.96 Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-4.2752347 - 6.535129
Average (Standard dev.)-0.0009133146 (±0.09016592)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 232.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61294_half_map_1.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Half map: #1

Fileemd_61294_half_map_2.map
Projections & Slices
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Sample components

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Entire : Protease Dimer

EntireName: Protease Dimer
Components
  • Complex: Protease Dimer
    • Protein or peptide: Core protease I7
    • Protein or peptide: A1ECL-DI8-ALA-AEM

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Supramolecule #1: Protease Dimer

SupramoleculeName: Protease Dimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all / Details: Protease Dimer in complex with compound A4
Source (natural)Organism: Monkeypox virus

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Macromolecule #1: Core protease I7

MacromoleculeName: Core protease I7 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
EC number: Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
Source (natural)Organism: Monkeypox virus
Molecular weightTheoretical: 49.088477 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MERYTDLVIS KIPELGFTNL LCHIYSLAGL CSNIDVSKFL TNCNGYVVEK YDKSTTAGKV SCIPIGMMLE LVESGHLSRP NSSDELDQK KELTDELTTR YHSIYDVFEL PTSIPLAYFF KPQLREKVSK AIDFSQMDLK IDDLSRKGIH TGENPKVVKM K IEPERGAW ...String:
MERYTDLVIS KIPELGFTNL LCHIYSLAGL CSNIDVSKFL TNCNGYVVEK YDKSTTAGKV SCIPIGMMLE LVESGHLSRP NSSDELDQK KELTDELTTR YHSIYDVFEL PTSIPLAYFF KPQLREKVSK AIDFSQMDLK IDDLSRKGIH TGENPKVVKM K IEPERGAW MSNRSIKNLV SQFAYGSEVD YIGQFDMRFL NSLAIHEKFD AFMNKHILSY ILKDKIKSST SRFVMFGFCY LS HWKCVIY DKKQCLVSFY DSGGNIPTEF HHYNNFYFYS FSDGFNTNHR HSVLDNTNCD IDVLFRFFEC TFGAKIGCIN VEV NQLLES ECGMFISLFM ILCTRTPPKS FKSLKKVYTF FKFLADKKMT LFKSILFNLQ DLSLYITETD NAGLKEYKRM EKWT KKSIN VICDKLTTKL NRIVDDDE

UniProtKB: MPXVgp068

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Macromolecule #2: A1ECL-DI8-ALA-AEM

MacromoleculeName: A1ECL-DI8-ALA-AEM / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 549.589 Da
SequenceString:
(A1ECL)(DI8)A(AEM)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 717581
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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