Dowarha Deepu, Chou Ruey-Hwang, Yu Chin
Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan.
ACS Omega. 2018 Aug 22;3(8):9689-9698. doi: 10.1021/acsomega.8b00922. eCollection 2018 Aug 31.
The Ca-sensing protein S100A11 of the S100 family is an important mediator of numerous biological functions and pathological conditions including cancer. The receptor for advanced glycation end products (RAGE) has been well accepted as the major receptor for several S100 family members. Here, we take the S100B protein as an antagonist to interfere with the interaction flanked by S100A11 and the RAGE V domain. We employed NMR spectroscopy to describe the interactions between the S100A11 and S100B proteins. H-N heteronuclear single-quantum correlation-NMR titrations showed the potential binding dynamics of S100A11 and S100B interactions. In the HADDOCK program, we constructed the S100A11-S100B heterodimer complex that was then superimposed with the S100A11-S100B complex structure in the same orientation as the S100A11-RAGE V domain complex. This overlay analysis showed that S100B could interfere in the binding section of S100A11 and the RAGE V domain. Additionally, water-soluble tetrazolium-1 assay provided a functional read-out of the effects of these proteins in an in vitro cancer model. Our study establishes that the development of an S100B antagonist could perform a vital part in the treatment of S100- and RAGE-dependent human diseases.
S100家族的钙传感蛋白S100A11是包括癌症在内的众多生物学功能和病理状况的重要介质。晚期糖基化终产物受体（RAGE）已被广泛认为是几种S100家族成员的主要受体。在这里，我们以S100B蛋白作为拮抗剂来干扰S100A11与RAGE V结构域之间的相互作用。我们采用核磁共振光谱来描述S100A11和S100B蛋白之间的相互作用。氢-氮异核单量子相关核磁共振滴定显示了S100A11和S100B相互作用的潜在结合动力学。在HADDOCK程序中，我们构建了S100A11-S100B异二聚体复合物，然后将其与S100A11-RAGE V结构域复合物以相同方向叠加S100A11-S100B复合物结构。这种叠加分析表明，S100B可以干扰S100A11与RAGE V结构域的结合区域。此外，水溶性四唑盐-1试验提供了这些蛋白质在体外癌症模型中作用的功能读数。我们的研究表明，S100B拮抗剂的开发可能在治疗S100和RAGE依赖性人类疾病中发挥重要作用。
