Grb2的SH2结构域的晶体结构：突出了一种新的高亲和力抑制剂的结合。,Journal of Molecular Biology

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Grb2的SH2结构域的晶体结构：突出了一种新的高亲和力抑制剂的结合。
Journal of Molecular Biology ( IF 4.7 ) Pub Date : 2002 Feb 1 , DOI: 10.1006/jmbi.2001.5299
Pierre Nioche , Wang-Qing Liu , Isabelle Broutin , Franck Charbonnier , Marie-Thérèse Latreille , Michel Vidal , Bernard Roques , Christiane Garbay , Arnaud Ducruix

生长因子受体的激活在其C端部分诱导酪氨酸残基的磷酸化，从而为含SH2结构域的蛋白质形成结合位点。Grb2是一种蛋白质，可募集Sos（Ras的交换因子）。招募Sos可以激活Ras和随后的信号传输。这促进了MAP激酶向核内的转运和早期转录因子的活化。Grb2是一种25 kDa的蛋白质，由一个被两个SH3域包围的SH2域组成。Grb2的SH2结构域以共有序列pYXNX结合II类磷酸酪氨酰肽。因此，Grb2是双功能衔接子蛋白的一个很好的例子，它使蛋白紧密靠近，从而允许信号转导通过位于不同区室的蛋白。为了探索Grb2和磷酸化的配体之间的相互作用，我们已经解决了Grb2-SH2域和对应于Shc衍生序列的肽之间的复合物的晶体结构。描述了两种结构：与PSpYVNVQN在1.5 A处复合的Grb2-SH2结构域；和与mAZ * -pY-（alphaMe）pY-N-NH2假肽复合的Grb2-SH2结构域在2 A时进行比较。两者都与在2.7 A下确定的未配体SH2结构进行了比较，有趣的是，该结构形成了二聚体通过两个与对称相关的分子的两个交换子域。mAZ-pY-（alphaMe）pY-N-NH2假肽对Grb2-SH2的纳摩尔亲和力与与非保守残基的新相互作用有关。防止与酪氨酸激酶蛋白或其他衔接子如Shc或IRS1相互作用的Grb2-SH2域抑制剂的设计应提供一种中断Ras信号通路的手段。新合成的伪肽对Grb2-SH2结构域表现出纳摩尔亲和力。这样就有可能设计出具有相似亲和力和更简单化学结构的新型抑制剂。

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Crystal structures of the SH2 domain of Grb2: highlight on the binding of a new high-affinity inhibitor.

The activation of growth factor receptors induces phosphorylation of tyrosine residues in its C-terminal part, creating binding sites for SH2 domain-containing proteins. Grb2 is a protein that recruits Sos, the exchange factor for Ras. Recruitment of Sos allows for Ras activation and subsequent signal transmission. This promotes translocation of MAP kinases into the nucleus and activation of early transcription factors. Grb2, a 25 kDa protein, is composed of one SH2 domain surrounded by two SH3 domains. The SH2 domain of Grb2 binds to class II phosphotyrosyl peptides with the consensus sequence pYXNX. Thus, Grb2 is a good example of a bifunctional adaptor protein that brings proteins into close proximity, allowing signal transduction through proteins located in different compartments. To explore the interactions between Grb2 and phosphorylated ligands, we have solved the crystal structure of complexes between the Grb2-SH2 domain and peptides corresponding to Shc-derived sequences. Two structures are described: the Grb2-SH2 domain in complex with PSpYVNVQN at 1.5 A; and the Grb2-SH2 domain in complex with mAZ*-pY-(alphaMe)pY-N-NH2 pseudo-peptide, at 2 A. 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.

更新日期：2017-01-31

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