4pid

Crystal structure of human adenovirus 2 protease with a weak pyrimidine nitrile inhibitor

spinqualitylabelsall models 4pid, resolution 1.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4pid is a 2 chain structure with sequence from Human adenovirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.59Å Ligands: 2UQ, ACT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PRO_ADE02 Cleaves viral precursor proteins (pTP, pIIIa, pVI, pVII, pVIII, and pX) inside newly assembled particles giving rise to mature virions. Protease complexed to its cofactor slides along the viral DNA to specifically locate and cleave the viral precursors. Mature virions have a weakened organization compared to the unmature virions, thereby facilitating subsequent uncoating. Without maturation, the particle lacks infectivity and is unable to uncoat. Late in adenovirus infection, in the cytoplasm, may participate in the cytoskeleton destruction. Cleaves host cells cytoskeletal keratins K7 and K18. Publication Abstract from PubMed 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. Discovery and structure-based optimization of adenain inhibitors.,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 ACS Med Chem Lett. 2014 Jun 20;5(8):937-41. doi: 10.1021/ml500224t. eCollection, 2014 Aug 14. PMID:25147618 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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