View source for 4pie


==Crystal structure of human adenovirus 2 protease a substrate based nitrile inhibitor==
<StructureSection load='4pie' size='340' side='right'caption='[[4pie]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4pie]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_adenovirus_2 Human adenovirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PIE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PIE FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.94&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3FO:N-{(2S)-2-(3-CHLOROPHENYL)-2-[(METHYLSULFONYL)AMINO]ACETYL}-L-PHENYLALANYL-N-[(2Z)-2-IMINOETHYL]GLYCINAMIDE'>3FO</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4pie FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pie OCA], [https://pdbe.org/4pie PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pie RCSB], [https://www.ebi.ac.uk/pdbsum/4pie PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pie ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PRO_ADE02 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.<ref>PMID:22791715</ref> 
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== 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<ref>PMID:25147618</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human adenovirus 2]]
[[Category: Large Structures]]
[[Category: Altmann E]]
[[Category: Bernardi A]]
[[Category: Combrink C]]
[[Category: Ellis D]]
[[Category: Erbel C]]
[[Category: Grosche P]]
[[Category: Hughes N]]
[[Category: Jarousse N]]
[[Category: Mac Sweeney A]]
[[Category: Melkko S]]
[[Category: Ramage P]]
[[Category: Sirockin F]]