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学科主题: 生命有机化学
题名: Structural basis of rasGRP binding to high-affinity PKC ligands
其他题名: Ras GRP与高亲合性蛋白激酶C配体结合的结构基础
作者: Ma DW(马大为)
刊名: J. Med. Chem.
发表日期: 2002
卷: 45, 期:4, 页:853-860
收录类别: SCI
部门归属: 中国科学院上海有机化学研究所生命有机化学实验室
英文摘要: The ras guanyl releasing protein RasGRP belongs to the CDC25 class of guanyl nucleotide exchange factors that regulate Ras-related GTPases. These GTPases serve as switches for the propagation and divergence of signaling pathways. One interesting feature of rasGRP is the presence of a C-terminal C1 domain, which has high homology to the PKC C1 domain and binds to diacylglycerol (DAG) and photbol esters. RasGRP thus represents novel, non-kinase phorbol ester receptor. In this pater, we investigate the binding of indolactam (V) (ILV), 7-(n-octyl)-ILV,8-(1-decynyl)benzolactam(V)(benzolactam), and 7-methoxy-8-(1-decynyl)benzolactam(V) (methoxylated benzolactam) to RasGRP through both experimental binding assays andmolecular modeling strudies. The binding affiniteis of these lactams to RasGRP are within the nanomolar range. Homology modeling was used to model the structure of the RasGRP Cl domain (Cl-RasGRP), which was subsequently used to model the structure of Cl-RASGRP in complex with these ligands and phorbol 13-acetate using a computational docking method. The structural model of Cl-RasGRP exhibits a folding pattern that is nearly identical to that of Clb-PKCδand is comprised of three antiparllel-strand β-sheets capped against a C-terminal α-helix. Two loops A and B comprising residues 8-12 and 21-27 form a binding pocket that has some positive charge character. The ligands phorbol 13-acetate, benzolactam. And ILV are recognized by Cl-RasGRP in complex with phorbol 13-acetate, benzolactam, and ILV, common hydrogen bonds are formed with two residues thr 12 and Leu21, whereas other hydrogen bond interactions are unique for each ligand. Furthermore, our modeling results suggest that the shallower insertion of ligands into the binding pocket of Cl-RasGRP compared to Clb-PKC δ may be due to the presence of Phe rater than Leu at position 20 in Cl-RasGRP. Taken together, our experimental and modeling studies provide us with a better understanding of the structural basis of the binding of PKC ligands to the novel phorbol ester receptor RasGRP.
语种: 英语
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WOS记录号: WOS:000173985300010
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内容类型: 期刊论文
URI标识: http://ir.sioc.ac.cn/handle/331003/15411
Appears in Collections:生命有机化学国家重点实验室_期刊论文

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Recommended Citation:
Ma DW. Structural basis of rasGRP binding to high-affinity PKC ligands[J]. J. Med. Chem.,2002,45(4):853-860.
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