Addressing Protein-Protein Interactions with Small Molecules: A Pro-Pro Dipeptide Mimic with a PPII Helix Conformation as a Module for the Synthesis of PRD-Binding Ligands
Addressing Protein-Protein Interactions with Small Molecules: A Pro-Pro Dipeptide Mimic with a PPII Helix Conformation as a Module for the Synthesis of PRD-Binding Ligands
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DOI：
10.1002/anie.201001739
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Schmalz, Hans-Guenther
中科院分区：
文献类型：
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作者：
Zaminer, Jan;Brockmann, Christoph;Schmalz, Hans-Guenther
富含脯氨酸的基序识别结构域(PRD)与富含PRM的蛋白质之间的相互作用在自然界中被广泛利用，并参与了几个相关的过程，如酪氨酸激酶受体信号、[1-3]内吞作用、[4]细胞骨架重排、[5，6]转录、[7]和剪接。[8，9]近年来，一些PRD被确定为可能的治疗靶点，可能通过合成的小分子来解决。它参与了酶活性的调节和信号复合体的组装。[8]所有PRM的一个共同属性是它们优先形成一个整体形状类似于三棱柱的左旋多聚脯氨酸II(PPII)螺旋(图1)。[9]这种结构元件具有9.3的螺旋间距，每转三个残基，典型的扭转角F为±758和Y
Interactions of so-called proline-rich motif-recognizing domains (PRDs) with proteins containing proline-rich motifs (PRMs) are widely utilized by nature and are involved in several relevant processes, such as tyrosine kinase receptor signaling,[1–3] endocytosis,[4] cytoskeletal rearrangements,[5, 6] transcription,[7] and splicing.[8, 9] In recent years, some PRDs were identified as putative therapeutical targets that can possibly be addressed by synthetic small molecules.[7] An example is the Fyn-SH3 domain, which is involved in the regulation of enzymatic activity and the assembly of signaling complexes.[8]A common property of all PRMs is that they preferentially form a left-handed polyproline type II (PPII) helix with an overall shape resembling a triangular prism (Figure 1).[9] This structural element has a helical pitch of 9.3, three residues per turn, and typical torsion angles F of À758 and Y