5IYT

Complex structure of EV-B93 main protease 3C with N-Ethyl 4-((1-cycloheptyl-1,2-dihydropyrazol-3-one-5-yl)-amino)-4-oxo-2Z-butenamide

Summary for 5IYT

• Entry DOI: 10.2210/pdb5iyt/pdb
• Related: 3Q3X 3Q3Y 3RUO
• Descriptor: EV-B93 main protease 3C, N-Ethyl 4-((1-cycloheptyl-1,2-dihydropyrazol-3-one-5-yl)-amino)-4-oxo-butanamide (3 entities in total)
• Functional Keywords: 3c main protease, enterovirus b93, covalent inhibitor, hydrolase
• Biological source: Echovirus 1 (strain Human/Egypt/Farouk/1951) (E-1)
• Cellular location: Capsid protein VP0: Virion . Capsid protein VP4: Virion . Capsid protein VP2: Virion . Capsid protein VP3: Virion . Capsid protein VP1: Virion . Protein 2B: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . Protein 2C: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . Protein 3A: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . Protein 3AB: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . Viral protein genome-linked: Virion . Protease 3C: Host cytoplasm . Protein 3CD: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . RNA-directed RNA polymerase: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side : O91734
• Total number of polymer chains: 2
• Total formula weight: 43113.43

Authors

Kaczmarska, Z.,Becker, D.,Rademann, J.,Coll, M. (deposition date: 2016-03-24, release date: 2016-10-05, Last modification date: 2024-01-10)

Primary citation

Becker, D.,Kaczmarska, Z.,Arkona, C.,Schulz, R.,Tauber, C.,Wolber, G.,Hilgenfeld, R.,Coll, M.,Rademann, J.
Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments.
Nat Commun, 7:12761-12761, 2016

PubMed Abstract: Small-molecule fragments binding to biomacromolecules can be starting points for the development of drugs, but are often difficult to detect due to low affinities. Here we present a strategy that identifies protein-binding fragments through their potential to induce the target-guided formation of covalently bound, irreversible enzyme inhibitors. A protein-binding nucleophile reacts reversibly with a bis-electrophilic warhead, thereby positioning the second electrophile in close proximity of the active site of a viral protease, resulting in the covalent de-activation of the enzyme. The concept is implemented for Coxsackie virus B3 3C protease, a pharmacological target against enteroviral infections. Using an aldehyde-epoxide as bis-electrophile, active fragment combinations are validated through measuring the protein inactivation rate and by detecting covalent protein modification in mass spectrometry. The structure of one enzyme-inhibitor complex is determined by X-ray crystallography. The presented warhead activation assay provides potent non-peptidic, broad-spectrum inhibitors of enteroviral proteases.

PubMed: 27677239
DOI: 10.1038/ncomms12761

Experimental method

X-RAY DIFFRACTION (1.73 Å)