4PIE

Crystal structure of human adenovirus 2 protease a substrate based nitrile inhibitor

Summary for 4PIE

• Entry DOI: 10.2210/pdb4pie/pdb
• Related: 4PIQ 4PIS
• Descriptor: Protease, Pre-protein VI, N-{(2S)-2-(3-chlorophenyl)-2-[(methylsulfonyl)amino]acetyl}-L-phenylalanyl-N-[(2Z)-2-iminoethyl]glycinamide, ... (7 entities in total)
• Functional Keywords: adenain, adenovirus, cofactor, pvic, cysteine protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human adenovirus 2 (HAdV-2); More
• Cellular location: Virion : P03252; Pre-protein VI: Host nucleus . Endosome lysis protein: Virion : P03274
• Total number of polymer chains: 2
• Total formula weight: 25292.56

Authors

Mac Sweeney, A.,Grosche, P.,Ellis, D.,Combrink, C.,Erbel, C.,Hughes, N.,Sirockin, F.,Melkko, S.,Bernardi, A.,Ramage, P.,Jarousse, N.,Altmann, E. (deposition date: 2014-05-08, release date: 2014-09-10, Last modification date: 2024-10-23)

Primary citation

Mac Sweeney, A.,Grosche, P.,Ellis, D.,Combrink, K.,Erbel, P.,Hughes, N.,Sirockin, F.,Melkko, S.,Bernardi, A.,Ramage, P.,Jarousse, N.,Altmann, E.
Discovery and structure-based optimization of adenain inhibitors.
Acs Med.Chem.Lett., 5:937-941, 2014

PubMed Abstract: The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2. The screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

PubMed: 25147618
DOI: 10.1021/ml500224t

Experimental method

X-RAY DIFFRACTION (1.94 Å)