中文摘要：

整合蛋白是一类重要的细胞表面黏附分子,由α和β亚基以非共价键结合而形成的异二聚体糖蛋白,对免疫反应、免疫细胞的组织定位、凝血、组织愈伤、癌细胞转移和新血管生成以及骨重塑等都至关重要。整合蛋白的功能依赖于对其配体结合的亲和性,以及所介导的下游信号通路。目前,对整合蛋白构象调节及亲和力调控机制已有深入了解。人类24种整合蛋白中,已有3种整合蛋白作为临床治疗靶点。这些药物以单克隆抗体、多肽和小分子化合物为主,均针对配体识别序列而设计。该类抑制剂往往具有部分激活的作用,直接导致药物的副反应和毒性。为了改善第一代整合蛋白药物的不足,目前基于晶体结构研究、虚拟筛选、高通量筛选以及基于结构设计的新型整合蛋白抑制剂,已经有许多进入临床试验。本文综述了一系列晶体结构中蛋白质与抑制剂的相互作用,以及借助晶体结构获得纯抑制剂为目的的实例,这些策略将会对开发新型有效的整合蛋白抑制剂提供很好的参考。

英文摘要：

Integrins are a family of α/β heterodimeric cell adhesion molecules,playing key roles in a number of important biological processes,such as immune responses,leukocyte trafficking,maintenance of tissue homeostasis,bone remodeling,cancer metastasis and angiogenesis.The function of integrins is dependent on the dynamic regulation of integrin affinity and its intracellular signaling.Studies have provided atomic level information on the integrin activation mechanism that results in it adopting a highaffinity ligand-binding conformation（s）.Of the 24 known human integrins,three are currently targeted therapeutically by monoclonal antibodies,peptides or small molecules,which based RGD-mimetic inhibitors.However,the RGD-mimetic inhibitors have been shown to cause partial agonism,leading to the opposite pharmacological effect.In order to explore a pure antagonist,most small-molecule integrin inhibitor leads are generally identified by high-throughput,virtual,or crystallography-based screening of compound libraries.Recently,a variety of new generation of inhibitor has emerged that lacks the RGDmimetic.This has been covered in a number of recent review articles.The analysis of protein-ligandinteractions of a number of selected crystal structures that have aided the engineering of designing of pure antagonist has been provided.Various tools and strategies described will be valuable for the development of new and more effective inhibitors.