8vqn

From Proteopedia

Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with small molecule 6R

PDB ID 8vqn

Drag the structure with the mouse to rotate

Structural highlights

8vqn is a 2 chain structure with sequence from Influenza A virus (A/Puerto Rico/8/1934(H1N1)). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.21Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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]

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. Ultrapotent influenza hemagglutinin fusion inhibitors developed through SuFEx-enabled high-throughput medicinal chemistry. Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2310677121. PMID:38753503 doi:10.1073/pnas.2310677121