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8J3T

Complex structure of human cytomegalovirus protease and a non-covalent small-molecule ligand

Summary for 8J3T
Entry DOI10.2210/pdb8j3t/pdb
DescriptorAssemblin, (4R)-1-[1-[(S)-[1-cyclopentyl-3-(2-methylphenyl)pyrazol-4-yl]-(4-methylphenyl)methyl]-2-oxidanylidene-pyridin-3-yl]-3-methyl-2-oxidanylidene-N-(3-oxidanylidene-2-azabicyclo[2.2.2]octan-4-yl)imidazolidine-4-carboxamide (3 entities in total)
Functional Keywordsprotease, hydrolase
Biological sourceHuman betaherpesvirus 5
Total number of polymer chains2
Total formula weight59637.03
Authors
Yoshida, S.,Sako, Y.,Nikaido, E.,Ueda, T.,Kozono, I.,Ichihashi, Y.,Nakahashi, A.,Onishi, M.,Yamatsu, Y.,Kato, T.,Nishikawa, J.,Tachibana, Y. (deposition date: 2023-04-18, release date: 2023-11-08, Last modification date: 2023-11-29)
Primary citationYoshida, S.,Sako, Y.,Nikaido, E.,Ueda, T.,Kozono, I.,Ichihashi, Y.,Nakahashi, A.,Onishi, M.,Yamatsu, Y.,Kato, T.,Nishikawa, J.,Tachibana, Y.
Peptide-to-Small Molecule: Discovery of Non-Covalent, Active-Site Inhibitors of beta-Herpesvirus Proteases.
Acs Med.Chem.Lett., 14:1558-1566, 2023
Cited by
PubMed Abstract: Viral proteases, the key enzymes that regulate viral replication and assembly, are promising targets for antiviral drug discovery. Herpesvirus proteases are enzymes with no crystallographically confirmed noncovalent active-site binders, owing to their shallow and polar substrate-binding pockets. Here, we applied our previously reported "Peptide-to-Small Molecule" strategy to generate novel inhibitors of β-herpesvirus proteases. Rapid selection with a display technology was used to identify macrocyclic peptide bound to the active site of human cytomegalovirus protease (HCMV) with high affinity, and pharmacophore queries were defined based on the results of subsequent intermolecular interaction analyses. Membrane-permeable small molecule , designed according to this hypothesis, exhibited enzyme inhibitory activity (IC = 10 to 10 M) against β-herpesvirus proteases, and the design concept was proved by X-ray cocrystal analysis.
PubMed: 37974946
DOI: 10.1021/acsmedchemlett.3c00359
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.9 Å)
Structure validation

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