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| | ==Crystal structure of human adenovirus 2 protease a substrate based nitrile inhibitor== | | ==Crystal structure of human adenovirus 2 protease a substrate based nitrile inhibitor== |
| - | <StructureSection load='4pie' size='340' side='right' caption='[[4pie]], [[Resolution|resolution]] 1.94Å' scene=''> | + | <StructureSection load='4pie' size='340' side='right'caption='[[4pie]], [[Resolution|resolution]] 1.94Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4pie]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Ade02 Ade02]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PIE FirstGlance]. <br> | + | <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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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> | + | </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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4piq|4piq]], [[4pis|4pis]]</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> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">L3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10515 ADE02])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Adenain Adenain], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.39 3.4.22.39] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4pie FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pie OCA], [http://pdbe.org/4pie PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pie RCSB], [http://www.ebi.ac.uk/pdbsum/4pie PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pie ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> [[http://www.uniprot.org/uniprot/CAP6_ADE02 CAP6_ADE02]] Pre-protein VI: During virus assembly, promotes hexon trimers nuclear import through nuclear pore complexes via an importin alpha/beta-dependent mechanism. By analogy to herpesviruses capsid assembly, might act as a scaffold protein to promote the formation of the icosahedral capsid.<ref>PMID:14633984</ref> <ref>PMID:15681401</ref> <ref>PMID:20333243</ref> <ref>PMID:20409568</ref> <ref>PMID:21209115</ref> <ref>PMID:21843868</ref> Endosome lysis protein: Structural component of the virion that provides increased stability to the particle shell through its interaction with the core-capsid bridging protein. Fibers shedding during virus entry into host cell allows the endosome lysis protein to be exposed as a membrane-lytic peptide. Exhibits pH-independent membrane fragmentation activity and probably mediates viral rapid escape from host endosome via organellar membrane lysis. It is not clear if it then remains partially associated with the capsid and involved in the intracellular microtubule-dependent transport of capsid to the nucleus, or if it is lost during endosomal penetration.<ref>PMID:14633984</ref> <ref>PMID:15681401</ref> <ref>PMID:20333243</ref> <ref>PMID:20409568</ref> <ref>PMID:21209115</ref> <ref>PMID:21843868</ref> Protease cofactor: Cofactor that activates the viral protease. Binds to viral protease in a 1:1 ratio.<ref>PMID:14633984</ref> <ref>PMID:15681401</ref> <ref>PMID:20333243</ref> <ref>PMID:20409568</ref> <ref>PMID:21209115</ref> <ref>PMID:21843868</ref> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ade02]] | + | [[Category: Human adenovirus 2]] |
| - | [[Category: Adenain]] | + | [[Category: Large Structures]] |
| - | [[Category: Altmann, E]] | + | [[Category: Altmann E]] |
| - | [[Category: Bernardi, A]] | + | [[Category: Bernardi A]] |
| - | [[Category: Combrink, C]] | + | [[Category: Combrink C]] |
| - | [[Category: Ellis, D]] | + | [[Category: Ellis D]] |
| - | [[Category: Erbel, C]] | + | [[Category: Erbel C]] |
| - | [[Category: Grosche, P]] | + | [[Category: Grosche P]] |
| - | [[Category: Hughes, N]] | + | [[Category: Hughes N]] |
| - | [[Category: Jarousse, N]] | + | [[Category: Jarousse N]] |
| - | [[Category: Melkko, S]] | + | [[Category: Mac Sweeney A]] |
| - | [[Category: Ramage, P]]
| + | [[Category: Melkko S]] |
| - | [[Category: Sirockin, F]]
| + | [[Category: Ramage P]] |
| - | [[Category: Sweeney, A Mac]]
| + | [[Category: Sirockin F]] |
| - | [[Category: Adenovirus]] | + | |
| - | [[Category: Cofactor]] | + | |
| - | [[Category: Cysteine protease]] | + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Pvic]]
| + | |
| Structural highlights
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.[1]
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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Perez-Berna AJ, Ortega-Esteban A, Menendez-Conejero R, Winkler DC, Menendez M, Steven AC, Flint SJ, de Pablo PJ, San Martin C. The role of capsid maturation on adenovirus priming for sequential uncoating. J Biol Chem. 2012 Sep 7;287(37):31582-95. doi: 10.1074/jbc.M112.389957. Epub 2012, Jul 12. PMID:22791715 doi:http://dx.doi.org/10.1074/jbc.M112.389957
- ↑ 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. 2014 Jun 20;5(8):937-41. doi: 10.1021/ml500224t. eCollection, 2014 Aug 14. PMID:25147618 doi:http://dx.doi.org/10.1021/ml500224t
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