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- PDB-9ku9: Structure of mpox core protease mutant -

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Basic information

Entry
Database: PDB / ID: 9ku9
TitleStructure of mpox core protease mutant
ComponentsMPXVgp068
KeywordsVIRAL PROTEIN / orthopoxvirus / mpox / protease
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
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.199 Å
AuthorsDong, X. / Wang, H. / Ji, X. / Gao, Y. / Wang, W. / Yang, H.
Funding support China, 1items
OrganizationGrant numberCountry
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
DepositionDec 3, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 24, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: MPXVgp068
C: MPXVgp068


Theoretical massNumber of molelcules
Total (without water)98,8062
Polymers98,8062
Non-polymers00
Water4,522251
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3160 Å2
ΔGint-33 kcal/mol
Surface area32050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.734, 113.500, 192.813
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein MPXVgp068 / Viral core cysteine proteinase


Mass: 49402.785 Da / Num. of mol.: 2 / Mutation: I215K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Monkeypox virus
Gene: MPXV-USA2003_099_GR-066, MPXV-USA2003_206_DM-066, MPXV-USA2003_223_RS-066, MPXV_USA2003_039_073, MPXV_USA2003_044_073
Production host: Escherichia coli (E. coli) / References: UniProt: Q3I7P9
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 251 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.37 Å3/Da / Density % sol: 48.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.2 M potassium sulfate, 20% w/v polyethylene glycol (PEG) 3350, pH 6.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 10, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.199→42.54 Å / Num. obs: 91758 / % possible obs: 99.9 % / Redundancy: 9.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.092 / Rrim(I) all: 0.097 / Net I/σ(I): 17.44
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.2-2.331.01477150.6411.1111
2.33-2.490.71173120.8750.7621
2.49-2.690.42968370.9590.4551
2.69-2.950.27262740.9880.2861
2.95-3.290.14957620.9960.1561
3.29-3.80.07850750.9980.0821
3.8-4.640.0543560.9990.0531
4.64-6.530.04734260.9990.051
6.53-42.540.03520510.9990.0371

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Processing

Software
NameVersionClassification
PHENIX(1.14_3260: ???)refinement
XDSdata scaling
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: AlphaFold

Resolution: 2.199→42.54 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.86 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2239 3759 4.1 %
Rwork0.188 --
obs0.1895 91699 99.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.199→42.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6021 0 0 251 6272
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0066167
X-RAY DIFFRACTIONf_angle_d0.7468302
X-RAY DIFFRACTIONf_dihedral_angle_d14.1613675
X-RAY DIFFRACTIONf_chiral_restr0.047907
X-RAY DIFFRACTIONf_plane_restr0.0051034
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.199-2.22640.34151350.32273091X-RAY DIFFRACTION94
2.2264-2.25570.34141380.29813226X-RAY DIFFRACTION97
2.2557-2.28660.29221340.29373171X-RAY DIFFRACTION99
2.2866-2.31930.32831370.2683223X-RAY DIFFRACTION100
2.3193-2.35390.311440.25763299X-RAY DIFFRACTION100
2.3539-2.39070.33011380.25533296X-RAY DIFFRACTION100
2.3907-2.42990.27391380.24383228X-RAY DIFFRACTION100
2.4299-2.47180.27061360.23293321X-RAY DIFFRACTION100
2.4718-2.51670.29441470.22613294X-RAY DIFFRACTION100
2.5167-2.56510.26431350.2183196X-RAY DIFFRACTION100
2.5651-2.61740.24031450.20063273X-RAY DIFFRACTION100
2.6174-2.67440.21021450.1873336X-RAY DIFFRACTION100
2.6744-2.73660.22431340.19243211X-RAY DIFFRACTION100
2.7366-2.8050.27111410.1953292X-RAY DIFFRACTION100
2.805-2.88080.2211370.18953288X-RAY DIFFRACTION100
2.8808-2.96560.23261400.18643259X-RAY DIFFRACTION100
2.9656-3.06120.1991430.18433335X-RAY DIFFRACTION100
3.0612-3.17060.20581330.18663203X-RAY DIFFRACTION100
3.1706-3.29750.25781400.18563346X-RAY DIFFRACTION100
3.2975-3.44750.20281350.18083204X-RAY DIFFRACTION100
3.4475-3.62920.20561410.17143296X-RAY DIFFRACTION100
3.6292-3.85640.22871400.16953291X-RAY DIFFRACTION100
3.8564-4.1540.23011410.16323228X-RAY DIFFRACTION100
4.154-4.57160.16591370.1463278X-RAY DIFFRACTION100
4.5716-5.23210.18221400.15883286X-RAY DIFFRACTION100
5.2321-6.58790.22481420.20583261X-RAY DIFFRACTION100
6.5879-42.540.19721430.1883208X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: -9.6342 Å / Origin y: -6.2534 Å / Origin z: -40.4007 Å
111213212223313233
T0.275 Å20.0008 Å2-0.0086 Å2-0.2726 Å20.0243 Å2--0.3077 Å2
L0.849 °20.1482 °2-0.7195 °2-0.1175 °2-0.1673 °2--1.0556 °2
S0.0021 Å °-0.076 Å °-0.0842 Å °0.0426 Å °0.0041 Å °-0.0014 Å °-0.1039 Å °0.0417 Å °-0.0181 Å °
Refinement TLS groupSelection details: all

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