2 BINDING ORIENTATIONS FOR PEPTIDES TO THE SRC SH3 DOMAIN - DEVELOPMENT OF A GENERAL-MODEL FOR SH3-LIGAND INTERACTIONS
2 BINDING ORIENTATIONS FOR PEPTIDES TO THE SRC SH3 DOMAIN - DEVELOPMENT OF A GENERAL-MODEL FOR SH3-LIGAND INTERACTIONS
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DOI：
10.1126/science.7526465
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发表时间：
1994-11-18
期刊：
影响因子：
56.9
通讯作者：
SCHREIBER, SL
中科院分区：
文献类型：
--
作者：
FENG, SB;CHEN, JK;SCHREIBER, SL
用核磁共振方法测定了两个Src同源3(SH3)结构域-配体络合物的溶液结构。每个复合体由SH3结构域和一个从组合合成制备的大量配体库中选择的富含9个氨基酸的脯氨酸多肽组成。结合的配体采用左手多脯氨酸II型(PPII)螺旋，尽管其螺旋的氨基到羧基的方向相反。多肽的方向是由配体的末端精氨酸残基和SH3结构域的保守天冬氨酸-99形成的盐桥决定的。这两个多肽第3、4、6和7位的残基也插入到配体结合部位；然而，在两个复合体中，各自的Pro和非Pro残基显示出互换的结合位置。这些结构结果导致了一个SH3结构域与富含Pro的多肽相互作用的模型，该模型可以用来预测未知结构的复合体中的关键残基。该模型被用来正确地识别来自核苷酸交换因子SOS与接头蛋白Grb2的氨基末端SH3结构域相关的多肽的结合方向以及接触和非接触残基。
Solution structures of two Src homology 3 (SH3) domain-ligand complexes have been determined by nuclear magnetic resonance. Each complex consists of the SH3 domain and a nine-residue proline-rich peptide selected from a large library of ligands prepared by combinatorial synthesis. The bound ligands adopt a left-handed polyproline type II (PPII) helix, although the amino to carboxyl directionalities of their helices are opposite. The peptide orientation is determined by a salt bridge formed by the terminal arginine residues of the ligands and the conserved aspartate-99 of the SH3 domain. Residues at positions 3, 4, 6, and 7 of both peptides also intercalate into the ligand-binding site; however, the respective proline and nonproline residues show exchanged binding positions in the two complexes. These structural results led to a model for the interactions of SH3 domains with proline-rich peptides that can be used to predict critical residues in complexes of unknown structure. The model was used to identify correctly both the binding orientation and the contact and noncontact residues of a peptide derived from the nucleotide exchange factor Sos in association with the amino-terminal SH3 domain of the adaptor protein Grb2.