Biology subjects

Ekundayo, B. E.

Publications and source records attributed to Ekundayo, B. E..

3 recordsLinked to original sources

bioRxiv2026

Temperature-dependent ligand relocation reveals plasticity of TRPM4 inhibition

Transient receptor potential melastatin 4 (TRPM4) is a Ca{superscript 2}-activated cation channel whose pharmacology is shaped by its molecular environment. It remains poorly understood how temperature and membrane context influence inhibitor recognition. Here we combine cryo-electron microscopy of membrane-derived vesicles and detergent-solubilized TRPM4 to investigate lipid-associated architecture and binding of the potent anthranilic anilide inhibitor PBA. We find that membrane vesicles preserve a native-like paralipid environment and reveal lipid binding patterns highly similar to those observed in GDN, supporting detergent-solubilized TRPM4 as a structurally relevant system for ligand analysis. Strikingly, PBA occupies distinct binding pockets at 8 {degrees}C and 37 {degrees}C. At low temperature, PBA binds in a previously described inhibitor pocket formed by S3, S4, the S4-S5 linker and the TRP helix, whereas at physiological temperature it relocates to a distinct site within the S1-S4 domain proximal to the Ca{superscript 2} regulatory region. These findings reveal temperature-dependent plasticity in TRPM4 ligand recognition.

biophysics↗

bioRxiv2025

Understanding the future risk of bat coronavirus spillover into humans: correlating sarbecovirus receptor usage, host range, and antigenicity.

Sarbecoviruses interact with their receptor, angiotensin converting enzyme 2 (ACE2), via the receptor binding domain (RBD) of Spike, the immunodominant target for neutralising antibodies. Understanding the interplay and correlation between ACE2-determined host range and antigenicity is vitally important for understanding the zoonotic potential of related bat sarbecoviruses. Using binding assays, pseudotype-entry assays and a diverse panel of mammalian ACE2 proteins, we examined the host range and related antigenicity of multiple bat coronaviruses. Broad bat ACE2 usage (a generalist phenotype) was most common in clade 1 sarbecoviruses, including SARS-CoV-2 and the BANAL isolates from Laos. In contrast, clade 3 (e.g., RhGB07) and 5 (e.g., Rc-o319) sarbecoviruses exhibited more restricted ACE2 usage (a specialist phenotype). A novel structure for RhGB07 Spike further helped to identify RBD residues associated with this receptor specialism. Interestingly, the generalist phenotypes were largely maintained with more diverse mammalian receptor libraries, including human, non-human primate, livestock, rodent ACE2 and potential intermediate reservoir hosts (e.g., civet, racoon dog, pangolin), while specialists, like RhGB07, exhibited wider phenotypic diversity. The impact of SARS-CoV-2s continued evolution in humans was also examined, identifying an expanding and/or shifting pattern of generalism for variants, especially Omicron and its sub-lineages. Furthermore, we compared and correlated these entry phenotypes with antigenicity using sera from SARS-CoV-2 convalescent individuals. Clade 1 viruses, phylogenetically related to SARS-CoV-2, were antigenically the most similar, with robust evidence for cross-neutralisation; however, there was still evidence for limited cross-neutralisation across the entire sub-genus. Finally, using monoclonal antibodies, derived from COVID-19 vaccinees with breakthrough infections, we pin-pointed the antibody epitope classes responsible for wider neutralisation. Our research indicates that generalist ACE2-using sarbecoviruses are phylogenetically and antigenically related to SARS-CoV-2.

microbiology↗

bioRxiv2023

Structure of a membrane-bound menaquinol:organohalide oxidoreductase

Organohalide-respiring bacteria are key organisms for the bioremediation of soils and aquifers contaminated with halogenated organic compounds. The major players in this process are respiratory reductive dehalogenases, corrinoid enzymes that use organohalides as substrates and contribute to energy conservation. Here, we present the first structure of a functional menaquinol:organohalide oxidoreductase (MOOR) obtained by cryo-EM. The membrane-bound protein was isolated from Desulfitobacterium hafniense strain TCE1 as a PceA2B2 complex catalysing the dechlorination of tetrachloroethene (PCE). Two catalytic PceA subunits are anchored to the membrane by two small integral membrane PceB subunits. The structure reveals two menaquinone molecules bound at the interface of the two different subunits, which are the starting point of a chain of redox cofactors for electron transfer to the active site. This structure elucidates how energy is conserved during organohalide respiration in menaquinone-dependent organohalide-respiring bacteria.

microbiology↗