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==Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors== | ==Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors== | ||
<StructureSection load='6ffs' size='340' side='right' caption='[[6ffs]], [[Resolution|resolution]] 1.86Å' scene=''> | <StructureSection load='6ffs' size='340' side='right'caption='[[6ffs]], [[Resolution|resolution]] 1.86Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6ffs]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FFS OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6ffs]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rhinovirus_A2 Rhinovirus A2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FFS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FFS FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D8E:~{N}-[(2~{S},5~{S},14~{S})-2-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-9-methyl-3,8,15-tris(oxidanylidene)-1,4,9-triazacyclopentadec-14-yl]-5-methyl-1,2-oxazole-3-carboxamide'>D8E</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.86Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D8E:~{N}-[(2~{S},5~{S},14~{S})-2-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-9-methyl-3,8,15-tris(oxidanylidene)-1,4,9-triazacyclopentadec-14-yl]-5-methyl-1,2-oxazole-3-carboxamide'>D8E</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6ffs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ffs OCA], [https://pdbe.org/6ffs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ffs RCSB], [https://www.ebi.ac.uk/pdbsum/6ffs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ffs ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/POLG_HRV2 POLG_HRV2] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The capsid interacts with human VLDLR to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin-mediated endocytosis. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.<ref>PMID:11034318</ref> <ref>PMID:12191477</ref> VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:11034318</ref> <ref>PMID:12191477</ref> Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.<ref>PMID:11034318</ref> <ref>PMID:12191477</ref> Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:11034318</ref> <ref>PMID:12191477</ref> Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity).<ref>PMID:11034318</ref> <ref>PMID:12191477</ref> Protein 3A, via its hydrophobic domain, serves as membrane anchor (By similarity).<ref>PMID:11034318</ref> <ref>PMID:12191477</ref> Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).<ref>PMID:11034318</ref> <ref>PMID:12191477</ref> RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:11034318</ref> <ref>PMID:12191477</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 18: | Line 19: | ||
</div> | </div> | ||
<div class="pdbe-citations 6ffs" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6ffs" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Human rhinovirus|Human rhinovirus]] | |||
*[[Virus protease 3D structures|Virus protease 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Rhinovirus A2]] | ||
[[Category: | [[Category: Farady C]] | ||
[[Category: | [[Category: Wiesmann C]] | ||
Latest revision as of 08:13, 21 November 2024
Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitorsStructure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors
Structural highlights
FunctionPOLG_HRV2 Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The capsid interacts with human VLDLR to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin-mediated endocytosis. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.[1] [2] VP0 precursor is a component of immature procapsids (By similarity).[3] [4] Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.[5] [6] Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).[7] [8] Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity).[9] [10] Protein 3A, via its hydrophobic domain, serves as membrane anchor (By similarity).[11] [12] Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).[13] [14] RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).[15] [16] Publication Abstract from PubMedThe design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub-micromolar antiviral activity. Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors.,Namoto K, Sirockin F, Sellner H, Wiesmann C, Villard F, Moreau RJ, Valeur E, Paulding SC, Schleeger S, Schipp K, Loup J, Andrews L, Swale R, Robinson M, Farady CJ Bioorg Med Chem Lett. 2018 Feb 1. pii: S0960-894X(18)30075-1. doi:, 10.1016/j.bmcl.2018.01.064. PMID:29433930[17] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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