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- EMDB-62520: Cryo-EM structure of MPXV core protease in complex with the subst... -

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Basic information

Entry
Database: EMDB / ID: EMD-62520
TitleCryo-EM structure of MPXV core protease in complex with the substrate derivative I-G18
Map data
Sample
  • Complex: DIMER
    • Protein or peptide: Core protease I7
  • Protein or peptide: Core protein VP8
KeywordsORTHOPOXVIRUSES / MONKEYPOX / PROTEASE / VIRAL REPLICATION / DRUG DISCOVERY / VIRAL PROTEIN
Function / homology
Function and homology information


cysteine-type peptidase activity / virion component / viral capsid / host cell cytoplasm / structural molecule activity / proteolysis
Similarity search - Function
Poxvirus VP8/L4R, nucleic acid binding / Poxvirus nucleic acid binding protein VP8/L4R / Peptidase C57, Vaccinia virus protein I7 / Vaccinia virus I7 processing peptidase / Papain-like cysteine peptidase superfamily
Similarity search - Domain/homology
Core protein VP8 / MPXVgp068
Similarity search - Component
Biological speciesMonkeypox virus
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsLan W / You T / Li D / Dong X / Wang H / Xu J / Wang W / Gao Y / Yang H
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81902063 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
DepositionNov 27, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62520.png

Downloads & links

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Map

FileDownload / File: emd_62520.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 300 pix.
= 246. Å		0.82 Å/pix.
x 300 pix.
= 246. Å		0.82 Å/pix.
x 300 pix.
= 246. Å

Surface

Projections

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Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-5.4745655 - 7.2373233
Average (Standard dev.)0.000038638394 (±0.1363759)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 246.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_62520_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_62520_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : DIMER

EntireName: DIMER
Components
  • Complex: DIMER
    • Protein or peptide: Core protease I7
  • Protein or peptide: Core protein VP8

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Supramolecule #1: DIMER

SupramoleculeName: DIMER / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: MONKEYPOX I7 IS A DIMER
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: Core protein VP8

MacromoleculeName: Core protein VP8 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Monkeypox virus
Molecular weightTheoretical: 1.127243 KDa
SequenceString:
IEEDTIFFA(ETA)

UniProtKB: Core protein VP8

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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 recording#0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K3 (6k x 4k) / #0 - Average electron dose: 60.0 e/Å2 / #1 - Image recording ID: 2 / #1 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #1 - 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

Image recording ID1
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 760440
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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