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- PDB-9ku2: Structure of taterapox core protease central domain -

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Basic information

Entry
Database: PDB / ID: 9ku2
TitleStructure of taterapox core protease central domain
ComponentsViral core cysteine proteinase
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 / Viral core cysteine proteinase
Function and homology information
Biological speciesTaterapox virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.895 Å
AuthorsLi, D. / 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

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Assembly

Deposited unit
A: Viral core cysteine proteinase


Theoretical massNumber of molelcules
Total (without water)49,4201
Polymers49,4201
Non-polymers00
Water4,414245
1
A: Viral core cysteine proteinase

A: Viral core cysteine proteinase


Theoretical massNumber of molelcules
Total (without water)98,8402
Polymers98,8402
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation1
Buried area1910 Å2
ΔGint-16 kcal/mol
Surface area17830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.900, 65.677, 95.881
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein Viral core cysteine proteinase


Mass: 49419.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Due to natural protein degradation, the molecular weight of the crystallised piece of protein is 23517 Da.
Source: (gene. exp.) Taterapox virus / Gene: TATV_DAH68_079 / Production host: Escherichia coli (E. coli) / References: UniProt: Q0NPD2
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 245 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN

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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: 2.67 Å3/Da / Density % sol: 53.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M sodium citrate, pH 5.5 and 15% w/v PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.97853 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: 0.97853 Å / Relative weight: 1
ReflectionResolution: 1.895→47.94 Å / Num. obs: 38629 / % possible obs: 99.9 % / Redundancy: 11.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.166 / Rrim(I) all: 0.174 / Net I/σ(I): 11.41
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.9-2.010.82532760.8720.8631
2.01-2.150.57230720.9370.5981
2.15-2.320.39428970.9650.4121
2.32-2.540.28326650.9850.2961
2.54-2.840.20924440.9890.2191
2.84-3.280.13621480.9950.1431
3.28-4.010.09618560.9970.1011
4.01-5.650.07714660.9970.0811
5.65-47.940.0728680.9970.0761

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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: 1.895→36.84 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 16.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1885 3742 9.69 %
Rwork0.1466 --
obs0.1507 38622 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.895→36.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1645 0 0 250 1895
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0191693
X-RAY DIFFRACTIONf_angle_d1.3542278
X-RAY DIFFRACTIONf_dihedral_angle_d11.784980
X-RAY DIFFRACTIONf_chiral_restr0.097236
X-RAY DIFFRACTIONf_plane_restr0.009287
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8951-1.91910.29991380.24211290X-RAY DIFFRACTION99
1.9191-1.94440.27731370.23121241X-RAY DIFFRACTION100
1.9444-1.9710.21871420.19771316X-RAY DIFFRACTION100
1.971-1.99910.25311440.18131308X-RAY DIFFRACTION100
1.9991-2.0290.2221340.18621270X-RAY DIFFRACTION100
2.029-2.06070.22881360.17751298X-RAY DIFFRACTION100
2.0607-2.09450.19451400.17291296X-RAY DIFFRACTION100
2.0945-2.13060.22541410.15641295X-RAY DIFFRACTION100
2.1306-2.16930.19021350.1621292X-RAY DIFFRACTION100
2.1693-2.2110.19751370.15491295X-RAY DIFFRACTION100
2.211-2.25620.22571440.16081304X-RAY DIFFRACTION100
2.2562-2.30520.18371350.15241263X-RAY DIFFRACTION100
2.3052-2.35880.19061390.15581336X-RAY DIFFRACTION100
2.3588-2.41780.19761340.14691278X-RAY DIFFRACTION100
2.4178-2.48320.23781420.14491302X-RAY DIFFRACTION100
2.4832-2.55620.18931410.1541271X-RAY DIFFRACTION100
2.5562-2.63870.19871360.14611288X-RAY DIFFRACTION100
2.6387-2.7330.18261440.13921309X-RAY DIFFRACTION100
2.733-2.84240.17951390.13951314X-RAY DIFFRACTION100
2.8424-2.97170.21161350.12691275X-RAY DIFFRACTION100
2.9717-3.12830.17841370.13131297X-RAY DIFFRACTION100
3.1283-3.32420.1781390.12541305X-RAY DIFFRACTION100
3.3242-3.58060.1631350.13011275X-RAY DIFFRACTION100
3.5806-3.94060.14181390.12281285X-RAY DIFFRACTION100
3.9406-4.50990.16351420.11011310X-RAY DIFFRACTION100
4.5099-5.67870.16431370.14051288X-RAY DIFFRACTION100
5.6787-36.840.19521400.1841279X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 6.0906 Å / Origin y: -0.112 Å / Origin z: 30.3616 Å
111213212223313233
T0.132 Å20.0071 Å2-0.0099 Å2-0.1342 Å20.0055 Å2--0.1355 Å2
L1.2276 °20.0638 °2-0.3151 °2-1.4667 °20.0777 °2--1.555 °2
S-0.0125 Å °0.0007 Å °-0.0392 Å °0.0353 Å °-0.0084 Å °-0.0896 Å °0.0915 Å °0.0075 Å °0.0207 Å °
Refinement TLS groupSelection details: all

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