Publications by authors named "Sally Kephart"
Visualizing intermediate stages of viral membrane fusion by cryo-electron tomography.
Trends Biochem Sci
October 2024
Article Synopsis
- Protein-mediated membrane fusion involves proteins undergoing significant shape changes to bring two membranes together, facilitating lipid mixing and creating a fusion pore.* -
- This process is crucial for enveloped viruses to enter host cells and deliver their genetic material.* -
- Recent cryo-electron microscopy studies are revealing detailed snapshots of viral fusion proteins in action, enhancing our understanding of the mechanisms behind this fusion process.*
Article Synopsis
- Influenza hemagglutinin (HA) is crucial for the virus's entry as it helps with receptor binding and fusion of membranes, with clear structures observed at two stages: prefusion and postfusion.
- Research has started to uncover the intermediate stages of HA during the fusion process, which aids in understanding its activation and how it changes shape to complete fusion.
- This study utilized hydrogen-deuterium exchange mass spectrometry to compare HA subtypes H1 and H3, revealing distinct behaviors in their structural changes during fusion, especially when influenced by a particular antibody.
Malaria transmission-blocking vaccines (TBVs) aim to elicit human antibodies that inhibit sporogonic development of Plasmodium falciparum in mosquitoes, thereby preventing onward transmission. Pfs48/45 is a leading clinical TBV candidate antigen and is recognized by the most potent transmission-blocking monoclonal antibody (mAb) yet described; still, clinical development of Pfs48/45 antigens has been hindered, largely by its poor biochemical characteristics. Here, we used structure-based computational approaches to design Pfs48/45 antigens stabilized in the conformation recognized by the most potently inhibitory mAb, achieving >25°C higher thermostability compared with the wild-type protein.
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- The envelope glycoprotein (Env) is crucial for HIV's ability to evade the immune system and is highly variable among different strains of the virus.
- Research using hydrogen/deuterium-exchange mass spectrometry (HDX-MS) indicates that the dynamics and structural flexibility of Env differ significantly across various HIV isolates.
- These differences affect neutralization sensitivity, receptor activation, and the stability of the Env trimer, with certain mutations stabilizing some isolates but having minimal impact on others.
Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an "open" state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We use homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the "closed" state, yielding two near-atomic resolution structures of NA by cryo-EM.
View Article and Find Full Text PDFInfluenza vaccines that confer broad and durable protection against diverse viral strains would have a major effect on global health, as they would lessen the need for annual vaccine reformulation and immunization. Here we show that computationally designed, two-component nanoparticle immunogens induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens contain 20 haemagglutinin glycoprotein trimers in an ordered array, and their assembly in vitro enables the precisely controlled co-display of multiple distinct haemagglutinin proteins in defined ratios.
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