The primary function of the monomorphic MHC class Ib molecule Qa-1b is to present peptides derived from the leader sequences of other MHC class I molecules for recognition by the CD94-NKG2 receptors expressed by NK and T cells. Whereas the mode of peptide presentation by its ortholog HLA-E, and subsequent recognition by CD94-NKG2A, is known, the molecular basis of Qa-1b function is unclear. We have assessed the interaction between Qa-1b and CD94-NKG2A and shown that they interact with an affinity of 17 μM. Furthermore, we have determined the structure of Qa-1b bound to the leader sequence peptide, Qdm (AMAPRTLLL), to a resolution of 1.9 Å and compared it with that of HLA-E. The crystal structure provided a basis for understanding the restricted peptide repertoire of Qa-1b. Whereas the Qa-1b-AMAPRTLLL complex was similar to that of HLA-E, significant sequence and structural differences were observed between the respective Ag-binding clefts. However, the conformation of the Qdm peptide bound by Qa-1b was very similar to that of peptide bound to HLA-E. Although a number of conserved innate receptors can recognize heterologous ligands from other species, the structural differences between Qa-1b and HLA-E manifested in CD94-NKG2A ligand recognition being species specific despite similarities in peptide sequence and conformation. Collectively, our data illustrate the structural homology between Qa-1b and HLA-E and provide a structural basis for understanding peptide repertoire selection and the specificity of the interaction of Qa-1b with CD94-NKG2 receptors.

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In this study we designed and synthesized a series of new hesperetin derivatives on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of the novel derivatives was also evaluated. Results showed that the synthesized hesperetin derivatives displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (selectivity index values from 68 to 305). The Lineweaver-Burk plot and molecular docking study showed that these compounds targeted both the peripheral anionic site (PAS) and catalytic active site (CAS) of AChE. The derivatives also showed a potent self-induced β-amyloid (Aβ) aggregation inhibition and a peroxyl radical absorbance activity. Moreover, compound 4f significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Cytotoxicity assay showed that the low concentration of the derivatives does not affect the viability of the SH-SY5Y neurons. Thus, these hesperetin derivatives are potential multifunctional agents for further development for the treatment of Alzheimer’s disease.

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