的晶体结构BMP-2: BMPR-IA复杂和BMP-2拮抗剂的生成。

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镍J,德雷尔可,Kirsch T,张琦

的晶体结构BMP-2: BMPR-IA复杂和BMP-2拮抗剂的生成。

中华骨科杂志。2001;83年增刊1 (Pt 1): S7-14。

PubMed ID

11263668 (在PubMed

]

文摘

背景:骨形成蛋白(bmp)和生长和分化的因素(gdf)属于大转化生长因子(及)总科的多功能细胞因子。信号的最佳管理需要绑定的BMP BMP BMPR-IA细胞表面受体,BMPR-IB, BMPR-II。类似于其他细胞因子、鉴定及总科中的表现出严格的特异性的相互作用,这可能是一个原因定性和定量细胞反应的差异。了解我国和gdf激活受体,重要的是要确定中的复合物的结构和绑定机制。我们使用BMP-2作为一个关键的代表bmp识别抗原表位I型和II型受体结合突变交互分析和解决了BMP2的晶体结构:BMPR-IA受体ectodomain复杂。方法:识别氨基酸侧链参与受体结合,体外诱变处理的集合人类BMP-2变体准备并受交互分析与使用的受体ectodomains BMPR-IA, BMPR-II, ActR-II固定化生物传感器系统。BMP-2变异的生物活性是衡量BMP-2依赖的表达碱性磷酸酶(ALP)在C2C12细胞。结晶,复杂BMP-2 ectodomain BMPR-IA成立于解决方案,纯化和结晶(12)进行描述。结果:中的交互分析BMP-2变异识别不同抗原表位的I型和II型受体结合。因为TGF-beta-like蛋白质的结构比较与一条生路,I型受体的结合抗原决定基的基础上其location-termed抗原决定基“手腕”。 The crystal structure of the BMP-2:BMPR-IA ectodomain complex revealed a key feature of the ligand-receptor interaction: a large hydrophobic residue (Phe85) within a hydrophobic patch of BMPR-IA fit into a hydrophobic pocket composed of residues of both BMP-2 monomers. A second epitope identified by alanine mutagenesis scanning was termed the "knuckle" epitope on the basis of its location on the outer side of the "finger" segments of BMP-2. Mutations in either the wrist epitope or the knuckle epitope produced variants with altered biological activities. Variants with antagonistic properties were exclusively generated by mutations in the knuckle epitope of BMP-2. CONCLUSIONS AND CLINICAL RELEVANCE: The identification and characterization of the two receptor binding epitopes in BMP-2 provide new insight into the primary steps of BMP-receptor activation. Because of the structural similarities between members of the TGF-beta superfamily, it can be assumed that the data presented in this work are transferable to other TGF-beta receptor systems. Because of the association with various diseases, the generation of antagonists of other TGF-beta superfamily members might generate potent tools for basic research and therapeutic approaches.

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药物靶点

药物	目标	类	生物	药理作用	行动
Dibotermin阿尔法	骨形态形成蛋白受体type-1A	蛋白质	人类	是的	配位体	细节