【摘要】：整合蛋白是一類(lèi)重要的細(xì)胞表面黏附分子,由α和β亞基以非共價(jià)鍵結(jié)合而形成的異二聚體糖蛋白,對(duì)免疫反應(yīng)、免疫細(xì)胞的組織定位、凝血、組織愈傷、癌細(xì)胞轉(zhuǎn)移和新血管生成以及骨重塑等都至關(guān)重要。整合蛋白的功能依賴(lài)于對(duì)其配體結(jié)合的親和性,以及所介導(dǎo)的下游信號(hào)通路。目前,對(duì)整合蛋白構(gòu)象調(diào)節(jié)及親和力調(diào)控機(jī)制已有深入了解。人類(lèi)24種整合蛋白中,已有3種整合蛋白作為臨床治療靶點(diǎn)。這些藥物以單克隆抗體、多肽和小分子化合物為主,均針對(duì)配體識(shí)別序列而設(shè)計(jì)。該類(lèi)抑制劑往往具有部分激活的作用,直接導(dǎo)致藥物的副反應(yīng)和毒性。為了改善第一代整合蛋白藥物的不足,目前基于晶體結(jié)構(gòu)研究、虛擬篩選、高通量篩選以及基于結(jié)構(gòu)設(shè)計(jì)的新型整合蛋白抑制劑,已經(jīng)有許多進(jìn)入臨床試驗(yàn)。本文綜述了一系列晶體結(jié)構(gòu)中蛋白質(zhì)與抑制劑的相互作用,以及借助晶體結(jié)構(gòu)獲得純抑制劑為目的的實(shí)例,這些策略將會(huì)對(duì)開(kāi)發(fā)新型有效的整合蛋白抑制劑提供很好的參考。
[Abstract]:Integrin is an important class of cell surface adhesion molecules. Heterodimeric glycoproteins formed by non-covalent binding of 偽 and 尾 subunits are very important for immune response, tissue localization, coagulation, tissue healing, cancer cell metastasis and neovascularization, and bone remodeling. The function of integrated protein depends on the affinity to its ligand binding and the downstream signal pathway mediated by it. At present, the conformational regulation and affinity regulation mechanism of integrated protein have been deeply understood. Of the 24 human integrins, 3 have been used as clinical therapeutic targets. These drugs are mainly monoclonal antibodies, peptides and small molecular compounds, all of which are designed for ligand recognition sequences. These inhibitors often have the effect of partial activation, which directly leads to the side effects and toxicity of drugs. In order to improve the shortcomings of the first generation of integrated protein drugs, many new integrated protein inhibitors based on crystal structure research, virtual screening, high throughput screening and structural design have been involved in clinical trials. In this paper, a series of interactions between proteins and inhibitors in crystal structures are reviewed, and some examples of obtaining pure inhibitors by means of crystal structures are reviewed. These strategies will provide a good reference for the development of new and effective integrated protein inhibitors.
【作者單位】： 紹興文理學(xué)院醫(yī)學(xué)院醫(yī)學(xué)實(shí)驗(yàn)中心;寧波大學(xué)應(yīng)用海洋生物技術(shù)教育部重點(diǎn)實(shí)驗(yàn)室;
【基金】：國(guó)家自然科學(xué)基金(No.20903058;No.40906080) 紹興文理學(xué)院項(xiàng)目(No.2015LG1011) 浙江省教育廳項(xiàng)目(No.Y201635696)資助~~
【分類(lèi)號(hào)】：R91

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