γ-aminobutyric acid Type-A (GABAA) αβδ receptors regulate neuronal excitability and contribute to sleep, mood and motor coordination. However, the molecular arrangements of these receptors and the basis of GABA activation and δ-selective drug modulation remain unclear. We solve cryo-EM structures of α4β3δ receptors in an α-β-α-β-δ arrangement that contains two GABA binding pockets. GABA binding supports a classical β-subunit tilt and an outward configuration of the β-subunit M2-M3 loops. However, the δ subunit M2-M3 loop is orientated inward and the 9’ activation gate in the pore is closed, consistent with the low efficacy for these receptors. Addition of a δ-selective positive allosteric modulator (PAM), DS2-Me, reveals binding to an α-δ pocket that causes the 9’ activation gate to open. In this work we provide key insights into the stoichiometry, arrangement and molecular modes of GABA activation and δ-selective modulation of these critical regulators of neuronal excitability. GABAA αβδ receptors regulate tonic inhibitory neurotransmission neuronal excitability and contribute to sleep, mood and motor coordination. Here, we show the subunit arrangement and molecular mechanism of modulation by a δ-subunit selective drug.
Stephanie A. Nestorow, Wan-Na Chen, D. Bertrand et al.· Nature Communications· 0 citations
Hepatitis C virus (HCV) remains a major global health challenge despite the availability of highly effective antiviral therapies, underscoring the need for a broadly protective vaccine. The envelope glycoprotein E2 is the principal target of neutralizing antibodies, yet the full repertoire of vulnerable epitopes and mechanisms of antibody-mediated neutralization remains incompletely understood. Here, we exploited the unique binding properties of camelid nanobodies to probe the antigenic landscape of HCV E2 beyond the immunodominant human antibody response. We isolated a diverse panel of E2-specific nanobodies, including broadly neutralizing antibodies with high-affinity cross-reactivity toward genetically diverse HCV isolates. By combining cross-neutralization assays, competition binding experiments, and high-resolution hydrogen–deuterium exchange mass spectrometry (HDX-MS), we identified three mechanistically distinct classes of neutralizing epitopes. While one class targets the canonical E2 neutralization face, a second class recognizes antigenic region 1 (AR1), independently validating and extending recent evidence that this region represents a functional site of viral vulnerability. These findings demonstrate that broadly neutralizing antibody responses extend beyond the canonical neutralization face and establish a broader framework for understanding HCV neutralization. More broadly, our study illustrates how alternative antibody repertoires can reveal functionally important antigenic surfaces that are underrepresented in conventional human antibody responses, providing new opportunities for the rational design of next-generation HCV vaccine immunogens.
The 3.0 Å cryo-electron microscopy apo-structure of the PGT enzyme WbaP from Escherichia coli, a UDP-galactose:undecaprenolphosphate galactose-1-phosphoryl transferase, provides new insights into the PGT family of enzymes.
M. Weckener, Audrey Le Bas, Philip N. Ward et al.· Open Biology· 0 citations
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