| 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] [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.[2] [3] [4] [5] [6] [7] 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.[8] [9] [10] [11] [12] [13] Protease cofactor: Cofactor that activates the viral protease. Binds to viral protease in a 1:1 ratio.[14] [15] [16] [17] [18] [19]
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[20]
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
- ↑ Wodrich H, Guan T, Cingolani G, Von Seggern D, Nemerow G, Gerace L. Switch from capsid protein import to adenovirus assembly by cleavage of nuclear transport signals. EMBO J. 2003 Dec 1;22(23):6245-55. PMID:14633984 doi:http://dx.doi.org/10.1093/emboj/cdg614
- ↑ Wiethoff CM, Wodrich H, Gerace L, Nemerow GR. Adenovirus protein VI mediates membrane disruption following capsid disassembly. J Virol. 2005 Feb;79(4):1992-2000. PMID:15681401 doi:http://dx.doi.org/10.1128/JVI.79.4.1992-2000.2005
- ↑ Wodrich H, Henaff D, Jammart B, Segura-Morales C, Seelmeir S, Coux O, Ruzsics Z, Wiethoff CM, Kremer EJ. A capsid-encoded PPxY-motif facilitates adenovirus entry. PLoS Pathog. 2010 Mar 19;6(3):e1000808. doi: 10.1371/journal.ppat.1000808. PMID:20333243 doi:http://dx.doi.org/10.1371/journal.ppat.1000808
- ↑ Maier O, Galan DL, Wodrich H, Wiethoff CM. An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature. Virology. 2010 Jun 20;402(1):11-9. doi: 10.1016/j.virol.2010.03.043. Epub 2010, Apr 20. PMID:20409568 doi:http://dx.doi.org/10.1016/j.virol.2010.03.043
- ↑ Moyer CL, Wiethoff CM, Maier O, Smith JG, Nemerow GR. Functional genetic and biophysical analyses of membrane disruption by human adenovirus. J Virol. 2011 Mar;85(6):2631-41. doi: 10.1128/JVI.02321-10. Epub 2011 Jan 5. PMID:21209115 doi:http://dx.doi.org/10.1128/JVI.02321-10
- ↑ Burckhardt CJ, Suomalainen M, Schoenenberger P, Boucke K, Hemmi S, Greber UF. Drifting motions of the adenovirus receptor CAR and immobile integrins initiate virus uncoating and membrane lytic protein exposure. Cell Host Microbe. 2011 Aug 18;10(2):105-17. doi: 10.1016/j.chom.2011.07.006. PMID:21843868 doi:http://dx.doi.org/10.1016/j.chom.2011.07.006
- ↑ Wodrich H, Guan T, Cingolani G, Von Seggern D, Nemerow G, Gerace L. Switch from capsid protein import to adenovirus assembly by cleavage of nuclear transport signals. EMBO J. 2003 Dec 1;22(23):6245-55. PMID:14633984 doi:http://dx.doi.org/10.1093/emboj/cdg614
- ↑ Wiethoff CM, Wodrich H, Gerace L, Nemerow GR. Adenovirus protein VI mediates membrane disruption following capsid disassembly. J Virol. 2005 Feb;79(4):1992-2000. PMID:15681401 doi:http://dx.doi.org/10.1128/JVI.79.4.1992-2000.2005
- ↑ Wodrich H, Henaff D, Jammart B, Segura-Morales C, Seelmeir S, Coux O, Ruzsics Z, Wiethoff CM, Kremer EJ. A capsid-encoded PPxY-motif facilitates adenovirus entry. PLoS Pathog. 2010 Mar 19;6(3):e1000808. doi: 10.1371/journal.ppat.1000808. PMID:20333243 doi:http://dx.doi.org/10.1371/journal.ppat.1000808
- ↑ Maier O, Galan DL, Wodrich H, Wiethoff CM. An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature. Virology. 2010 Jun 20;402(1):11-9. doi: 10.1016/j.virol.2010.03.043. Epub 2010, Apr 20. PMID:20409568 doi:http://dx.doi.org/10.1016/j.virol.2010.03.043
- ↑ Moyer CL, Wiethoff CM, Maier O, Smith JG, Nemerow GR. Functional genetic and biophysical analyses of membrane disruption by human adenovirus. J Virol. 2011 Mar;85(6):2631-41. doi: 10.1128/JVI.02321-10. Epub 2011 Jan 5. PMID:21209115 doi:http://dx.doi.org/10.1128/JVI.02321-10
- ↑ Burckhardt CJ, Suomalainen M, Schoenenberger P, Boucke K, Hemmi S, Greber UF. Drifting motions of the adenovirus receptor CAR and immobile integrins initiate virus uncoating and membrane lytic protein exposure. Cell Host Microbe. 2011 Aug 18;10(2):105-17. doi: 10.1016/j.chom.2011.07.006. PMID:21843868 doi:http://dx.doi.org/10.1016/j.chom.2011.07.006
- ↑ Wodrich H, Guan T, Cingolani G, Von Seggern D, Nemerow G, Gerace L. Switch from capsid protein import to adenovirus assembly by cleavage of nuclear transport signals. EMBO J. 2003 Dec 1;22(23):6245-55. PMID:14633984 doi:http://dx.doi.org/10.1093/emboj/cdg614
- ↑ Wiethoff CM, Wodrich H, Gerace L, Nemerow GR. Adenovirus protein VI mediates membrane disruption following capsid disassembly. J Virol. 2005 Feb;79(4):1992-2000. PMID:15681401 doi:http://dx.doi.org/10.1128/JVI.79.4.1992-2000.2005
- ↑ Wodrich H, Henaff D, Jammart B, Segura-Morales C, Seelmeir S, Coux O, Ruzsics Z, Wiethoff CM, Kremer EJ. A capsid-encoded PPxY-motif facilitates adenovirus entry. PLoS Pathog. 2010 Mar 19;6(3):e1000808. doi: 10.1371/journal.ppat.1000808. PMID:20333243 doi:http://dx.doi.org/10.1371/journal.ppat.1000808
- ↑ Maier O, Galan DL, Wodrich H, Wiethoff CM. An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature. Virology. 2010 Jun 20;402(1):11-9. doi: 10.1016/j.virol.2010.03.043. Epub 2010, Apr 20. PMID:20409568 doi:http://dx.doi.org/10.1016/j.virol.2010.03.043
- ↑ Moyer CL, Wiethoff CM, Maier O, Smith JG, Nemerow GR. Functional genetic and biophysical analyses of membrane disruption by human adenovirus. J Virol. 2011 Mar;85(6):2631-41. doi: 10.1128/JVI.02321-10. Epub 2011 Jan 5. PMID:21209115 doi:http://dx.doi.org/10.1128/JVI.02321-10
- ↑ Burckhardt CJ, Suomalainen M, Schoenenberger P, Boucke K, Hemmi S, Greber UF. Drifting motions of the adenovirus receptor CAR and immobile integrins initiate virus uncoating and membrane lytic protein exposure. Cell Host Microbe. 2011 Aug 18;10(2):105-17. doi: 10.1016/j.chom.2011.07.006. PMID:21843868 doi:http://dx.doi.org/10.1016/j.chom.2011.07.006
- ↑ 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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