Altered receptor binding, antibody evasion and retention of T cell recognition by the SARS-CoV-2 XBB.1.5 spike protein.

The XBB.1.5 variant of SARS-CoV-2 has rapidly achieved global dominance and exhibits a high growth advantage over previous variants. Preliminary reports suggest that the success of XBB.1.5 stems from mutations within its spike glycoprotein, causing immune evasion and enhanced receptor binding. We present receptor binding studies that demonstrate retention of binding contacts with the human ACE2 receptor and a striking decrease in binding to mouse ACE2 due to the revertant R493Q mutation. Despite extensive evasion of antibody binding, we highlight a region on the XBB.1.5 spike protein receptor binding domain (RBD) that is recognized by serum antibodies from a donor with hybrid immunity, collected prior to the emergence of the XBB.1.5 variant. T cell assays reveal high frequencies of XBB.1.5 spike-specific CD4+ and CD8+ T cells amongst donors with hybrid immunity, with the CD4+ T cells skewed towards a Th1 cell phenotype and having attenuated effector cytokine secretion as compared to ancestral spike protein-specific cells. Thus, while the XBB.1.5 variant has retained efficient human receptor binding and gained antigenic alterations, it remains susceptible to recognition by T cells induced via vaccination and previous infection.

Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives.

The coordinated release of Ca2+ from the sarcoplasmic reticulum (SR) is critical for excitation-contraction coupling. This release is facilitated by ryanodine receptors (RyRs) that are embedded in the SR membrane. In skeletal muscle, activity of RyR1 is regulated by metabolites such as ATP, which upon binding increase channel open probability (Po). To obtain structural insights into the mechanism of RyR1 priming by ATP, we determined several cryo-EM structures of RyR1 bound individually to ATP-γ-S, ADP, AMP, adenosine, adenine, and cAMP. We demonstrate that adenine and adenosine bind RyR1, but AMP is the smallest ATP derivative capable of inducing long-range (>170 Å) structural rearrangements associated with channel activation, establishing a structural basis for key binding site interactions that are the threshold for triggering quaternary structural changes. Our finding that cAMP also induces these structural changes and results in increased channel opening suggests its potential role as an endogenous modulator of RyR1 conductance.

Structural analysis of receptor engagement and antigenic drift within the BA.2 spike protein.

The BA.2 sub-lineage of the Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant rapidly supplanted the original BA.1 sub-lineage in early 2022. Both lineages threatened the efficacy of vaccine-elicited antibodies and acquired increased binding to several mammalian ACE2 receptors. Cryoelectron microscopy (cryo-EM) analysis of the BA.2 spike (S) glycoprotein in complex with mouse ACE2 (mACE2) identifies BA.1- and BA.2-mutated residues Q493R, N501Y, and Y505H as complementing non-conserved residues between human and mouse ACE2, rationalizing the enhanced S protein-mACE2 interaction for Omicron variants. Cryo-EM structures of the BA.2 S-human ACE2 complex and of the extensively mutated BA.2 amino-terminal domain (NTD) reveal a dramatic reorganization of the highly antigenic N1 loop into a ß-strand, providing an explanation for decreased binding of the BA.2 S protein to antibodies isolated from BA.1-convalescent patients. Our analysis reveals structural mechanisms underlying the antigenic drift in the rapidly evolving Omicron variant landscape.