S100B作为拮抗剂来干扰S100A11和RAGE V域所包围的接口区域,ACS Omega

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S100B作为拮抗剂来干扰S100A11和RAGE V域所包围的接口区域
ACS Omega ( IF 3.7 ) Pub Date : 2018-08-22 00:00:00 , DOI: 10.1021/acsomega.8b00922
Deepu Dowarha,Ruey-Hwang Chou,Chin Yu

S100家族的Ca ²⁺感应蛋白S100A11是许多生物学功能和病理状况（包括癌症）的重要介体。晚期糖基化终产物（RAGE）的受体已被公认为几个S100家族成员的主要受体。在这里，我们以S100B蛋白为拮抗剂来干扰S100A11和RAGE V结构域侧翼的相互作用。我们使用核磁共振光谱来描述S100A11和S100B蛋白之间的相互作用。¹ H– ¹⁵N异核单量子相关核磁共振滴定表明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，然后以与S100A11–RAGE V域复合物相同的方向将其与S100A11–S100B复合物结构叠加。该重叠分析表明，S100B可能干扰S100A11与RAGE V结构域的结合部分。此外，水溶性四唑鎓-1测定法可提供这些蛋白质在体外癌症模型中作用的功能性读数。我们的研究建立了S100B拮抗剂的开发可以在依赖S100和RAGE的人类疾病的治疗中发挥至关重要的作用。

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S100B as an Antagonist To Interfere with the Interface Area Flanked by S100A11 and RAGE V Domain

The Ca²⁺-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. ¹H–¹⁵N 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.

更新日期：2018-08-22

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