Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei, 115, Taiwan.
Department of Chemistry, National Dong Hwa University, No. 1, Section 2, Da Hsueh Road, Shoufeng, Hualien, 974, Taiwan.
Angew Chem Int Ed Engl. 2017 Apr 3;56(15):4192-4196. doi: 10.1002/anie.201612518. Epub 2017 Mar 15.
Heparin-binding hemagglutinin (HBHA) is a 199 amino acid virulence factor at the envelope of Mycobacterium tuberculosis that contributes to latent tuberculosis. The binding of HBHA to respiratory epithelial cells, which leads to extrapulmonary dissemination of the pathogen, is mediated by cell-surface heparan sulfate (HS). We report the structural characterization of the HBHA/HS complex by NMR spectroscopy. To develop a model for the molecular recognition, the first chemically synthesized uniformly C- and N-labeled HS octasaccharide and a uniformly C- and N-labeled form of HBHA were prepared. Residues 180-195 at the C-terminal region of HBHA show large chemical shift perturbation upon association with the octasaccharide. Molecular dynamics simulations conforming to the multidimensional NMR data revealed key electrostatic and even hydrophobic interactions between the binding partners that may aid in the development of agents targeting the binding event.
肝素结合血凝素 (HBHA) 是结核分枝杆菌包膜上的一种 199 个氨基酸的毒力因子，有助于潜伏性结核的发生。HBHA 与呼吸道上皮细胞的结合导致病原体向肺外播散，这一过程由细胞表面的肝素硫酸盐 (HS) 介导。我们通过 NMR 光谱法对 HBHA/HS 复合物进行了结构特征描述。为了建立分子识别模型，我们首次制备了化学合成的、均一 C 和 N 标记的 HS 八聚糖以及均一 C 和 N 标记的 HBHA 形式。HBHA 的 C 末端区域的残基 180-195 在与八聚糖结合时表现出较大的化学位移扰动。符合多维 NMR 数据的分子动力学模拟揭示了结合物之间的关键静电相互作用，甚至是疏水相互作用，这可能有助于开发针对结合事件的靶向药物。
