8sd4: Difference between revisions
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The | ==Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with small molecule fusion inhibitor compound 7== | ||
<StructureSection load='8sd4' size='340' side='right'caption='[[8sd4]], [[Resolution|resolution]] 3.11Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8sd4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Puerto_Rico/8/1934(H1N1)) Influenza A virus (A/Puerto Rico/8/1934(H1N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8SD4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SD4 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]] 3.11Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZW4:(S~1~S)-N-{3,5-dichloro-4-[(2S)-2-phenylmorpholine-4-carbonyl]phenyl}-3-[(dimethylamino)methyl]azetidine-1-sulfonimidoyl+fluoride'>ZW4</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=8sd4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sd4 OCA], [https://pdbe.org/8sd4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sd4 RCSB], [https://www.ebi.ac.uk/pdbsum/8sd4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sd4 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/HEMA_I34A1 HEMA_I34A1] Binds to sialic acid-containing receptors on the cell surface, bringing about the attachment of the virus particle to the cell. This attachment induces virion internalization either through clathrin-dependent endocytosis or through clathrin- and caveolin-independent pathway. Plays a major role in the determination of host range restriction and virulence. Class I viral fusion protein. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in HA2, releasing the fusion hydrophobic peptide. Several trimers are required to form a competent fusion pore.[HAMAP-Rule:MF_04072] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Seasonal and pandemic-associated influenza strains cause highly contagious viral respiratory infections that can lead to severe illness and excess mortality. Here, we report on the optimization of our small-molecule inhibitor F0045(S) targeting the influenza hemagglutinin (HA) stem with our Sulfur-Fluoride Exchange (SuFEx) click chemistry-based high-throughput medicinal chemistry (HTMC) strategy. A combination of SuFEx- and amide-based lead molecule diversification and structure-guided design led to identification and validation of ultrapotent influenza fusion inhibitors with subnanomolar EC(50) cellular antiviral activity against several influenza A group 1 strains. X-ray structures of six of these compounds with HA indicate that the appended moieties occupy additional pockets on the HA surface and increase the binding interaction, where the accumulation of several polar interactions also contributes to the improved affinity. The compounds here represent the most potent HA small-molecule inhibitors to date. Our divergent HTMC platform is therefore a powerful, rapid, and cost-effective approach to develop bioactive chemical probes and drug-like candidates against viral targets. | |||
Ultrapotent influenza hemagglutinin fusion inhibitors developed through SuFEx-enabled high-throughput medicinal chemistry.,Kitamura S, Lin TH, Lee CD, Takamura A, Kadam RU, Zhang D, Zhu X, Dada L, Nagai E, Yu W, Yao Y, Sharpless KB, Wilson IA, Wolan DW Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2310677121. doi: , 10.1073/pnas.2310677121. Epub 2024 May 16. PMID:38753503<ref>PMID:38753503</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Kadam | <div class="pdbe-citations 8sd4" style="background-color:#fffaf0;"></div> | ||
[[Category: Wilson | == References == | ||
[[Category: Zhu | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Kadam RU]] | |||
[[Category: Wilson IA]] | |||
[[Category: Zhu X]] | |||
Latest revision as of 08:18, 5 June 2024
Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with small molecule fusion inhibitor compound 7Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with small molecule fusion inhibitor compound 7
Structural highlights
FunctionHEMA_I34A1 Binds to sialic acid-containing receptors on the cell surface, bringing about the attachment of the virus particle to the cell. This attachment induces virion internalization either through clathrin-dependent endocytosis or through clathrin- and caveolin-independent pathway. Plays a major role in the determination of host range restriction and virulence. Class I viral fusion protein. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in HA2, releasing the fusion hydrophobic peptide. Several trimers are required to form a competent fusion pore.[HAMAP-Rule:MF_04072] Publication Abstract from PubMedSeasonal and pandemic-associated influenza strains cause highly contagious viral respiratory infections that can lead to severe illness and excess mortality. Here, we report on the optimization of our small-molecule inhibitor F0045(S) targeting the influenza hemagglutinin (HA) stem with our Sulfur-Fluoride Exchange (SuFEx) click chemistry-based high-throughput medicinal chemistry (HTMC) strategy. A combination of SuFEx- and amide-based lead molecule diversification and structure-guided design led to identification and validation of ultrapotent influenza fusion inhibitors with subnanomolar EC(50) cellular antiviral activity against several influenza A group 1 strains. X-ray structures of six of these compounds with HA indicate that the appended moieties occupy additional pockets on the HA surface and increase the binding interaction, where the accumulation of several polar interactions also contributes to the improved affinity. The compounds here represent the most potent HA small-molecule inhibitors to date. Our divergent HTMC platform is therefore a powerful, rapid, and cost-effective approach to develop bioactive chemical probes and drug-like candidates against viral targets. Ultrapotent influenza hemagglutinin fusion inhibitors developed through SuFEx-enabled high-throughput medicinal chemistry.,Kitamura S, Lin TH, Lee CD, Takamura A, Kadam RU, Zhang D, Zhu X, Dada L, Nagai E, Yu W, Yao Y, Sharpless KB, Wilson IA, Wolan DW Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2310677121. doi: , 10.1073/pnas.2310677121. Epub 2024 May 16. PMID:38753503[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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