UCIBIO, REQUIMTE, Departamento de Quimica, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516, Caparica, Portugal.
CIC bioGUNE, Bizkaia, Technology Park, Building 801A, 48170, Derio, Spain.
Chemistry. 2021 May 20;27(29):7951-7958. doi: 10.1002/chem.202100800. Epub 2021 Apr 30.
Interactions of glycan-specific epitopes to human lectin receptors represent novel immune checkpoints for investigating cancer and infection diseases. By employing a multidisciplinary approach that combines isothermal titration calorimetry, NMR spectroscopy, molecular dynamics simulations, and X-ray crystallography, we investigated the molecular determinants that govern the recognition of the tumour and pathogenic glycobiomarker LacdiNAc (GalNAcβ1-4GlcNAc, LDN), including their comparison with the ubiquitous LacNAc epitope (Galβ1-4GlcNAc, LN), by two human immune-related lectins, galectin-3 (hGal-3) and the macrophage galactose C-type lectin (hMGL). A different mechanism of binding and interactions was observed for the hGal-3/LDN and hMGL/LDN complexes, which explains the remarkable difference in the binding specificity of LDN and LN by these two lectins. The new structural clues reported herein are fundamental for the chemical design of mimetics targeting hGal-3/hMGL recognition process.
糖基特异性表位与人类凝集素受体的相互作用代表了用于研究癌症和感染性疾病的新型免疫检查点。通过采用结合等温滴定量热法、NMR 光谱学、分子动力学模拟和 X 射线晶体学的多学科方法，我们研究了控制肿瘤和致病性糖生物标志物 LacdiNAc（GalNAcβ1-4GlcNAc，LDN）识别的分子决定因素，包括将其与无处不在的 LacNAc 表位（Galβ1-4GlcNAc，LN）进行比较，由两种人类免疫相关凝集素，半乳糖凝集素-3（hGal-3）和巨噬细胞半乳糖 C 型凝集素（hMGL）。观察到 hGal-3/LDN 和 hMGL/LDN 复合物的结合和相互作用的不同机制，这解释了这两种凝集素对 LDN 和 LN 结合特异性的显著差异。本文报道的新结构线索对于针对 hGal-3/hMGL 识别过程的模拟物的化学设计具有重要意义。
