水晶的SH2结构域Grb2:突出的高亲和性抑制剂的绑定一个新的。
文章的细节
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引用
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Nioche P刘WQ Broutin我Charbonnier F,有山,比达尔,罗格B, C Garbay, Ducruix
水晶的SH2结构域Grb2:突出的高亲和性抑制剂的绑定一个新的。
J杂志。2002年2月1日,315 (5):1167 - 77。
- PubMed ID
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11827484 (在PubMed]
- 文摘
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生长因子受体的激活诱导的酪氨酸残基磷酸化c端部分,创建绑定网站SH2 domain-containing蛋白质。新兵Sos Grb2是一种蛋白质,Ras的交换因素。招聘Sos允许Ras激活和随后的信号传输。这可以促进易位的激酶映射到细胞核和早期转录因子的激活。Grb2, 25 kDa蛋白质,是由一个SH2域两个SH3区域包围。的SH2领域Grb2结合二类phosphotyrosyl肽序列pYXNX与共识。因此,Grb2是一个很好的例子,一个双官能适配器蛋白质,蛋白质进近,允许通过信号转导蛋白位于不同的隔间。探讨Grb2和磷酸化配体之间的相互作用,我们已经解决了配合物的晶体结构之间的Grb2-SH2域和相应肽Shc-derived序列。两个结构描述:Grb2-SH2域在复杂PSpYVNVQN 1.5;和Grb2-SH2域在复杂与玛斯* py - (alphaMe) pY-N-NH2 pseudo-peptide, 2。 Both are compared to an unliganded SH2 structure determined at 2.7 A which, interestingly enough, forms a dimer through two swapping subdomains from two symmetry-related molecules. The nanomolar affinity of the mAZ-pY-(alphaMe)pY-N-NH2 pseudo-peptide for Grb2-SH2 is related to new interactions with non- conserved residues. The design of Grb2-SH2 domain inhibitors that prevent interaction with tyrosine kinase proteins or other adaptors like Shc or IRS1 should provide a means to interrupt the Ras signaling pathway. Newly synthesized pseudo-peptides exhibit nanomolar affinities for the Grb2-SH2 domain. It will then be possible to design new inhibitors with similar affinity and simpler chemical structures.