Dalgarno D C, Botfield M C, Rickles R J
ARIAD Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Biopolymers. 1997;43(5):383-400. doi: 10.1002/(SICI)1097-0282(1997)43:5<383::AID-BIP4>3.0.CO;2-R.
The ligand binding preferences, structural features, and biological function of SH3 (Src homology 3) domains are discussed. SH3 domains bind "core" Pro-rich peptide ligands (7-9 amino acids in length) in a polyproline II helical conformation in a highly conserved aromatic rich patch on the protein surface (approximately 390 A2). The ligands can interact with the protein in one of two orientations, depending on the position (N- vs C-terminal) of ligand residues binding to the SH3 selectivity pocket. Core SH3 ligands are characterized by relatively weak interactions (KD = 5-100 microM) that show little binding selectivity within SH3 families. Higher affinity, more selective contiguous ligands require additional flanking residues that bind to less conserved portions of the SH3 surface, with corresponding increase in ligand size and complexity. In contrast to peptide ligands, protein ligands of SH3 domains can exploit multiple discontiguous interactions to enhance affinity and selectivity. A protein-SH3 interaction that utilizes unique interactions may permit the design of small high affinity SH3 ligands. At present, the extended nature of the binding site and homologous nature of the core binding region among SH3 domains present key challenges for structure-based drug design.
本文讨论了SH3（Src同源结构域3）结构域的配体结合偏好、结构特征和生物学功能。SH3结构域在蛋白质表面高度保守的富含芳香族氨基酸的区域（约390 Ų），以多聚脯氨酸II螺旋构象结合“核心”富含脯氨酸的肽配体（长度为7 - 9个氨基酸）。根据配体残基与SH3选择性口袋结合的位置（N端与C端），配体可以以两种方向之一与蛋白质相互作用。核心SH3配体的特征是相互作用相对较弱（解离常数KD = 5 - 100 μM），在SH3家族中几乎没有结合选择性。更高亲和力、更具选择性的连续配体需要额外的侧翼残基，这些残基与SH3表面不太保守的部分结合，同时配体的大小和复杂性相应增加。与肽配体不同，SH3结构域的蛋白质配体可以利用多个不连续的相互作用来增强亲和力和选择性。利用独特相互作用的蛋白质 - SH3相互作用可能允许设计小的高亲和力SH3配体。目前，SH3结构域之间结合位点的扩展性和核心结合区域的同源性给基于结构的药物设计带来了关键挑战。
