Artificial human Met agonists based on macrocycle scaffolds.
Artificial human Met agonists based on macrocycle scaffolds.
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DOI：
10.1038/ncomms7373
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发表时间：
2015-03-11
影响因子：
16.6
通讯作者：
Suga, Hiroaki
中科院分区：
文献类型：
--
作者：
Ito, Kenichiro;Sakai, Katsuya;Suzuki, Yoshinori;Ozawa, Naoya;Hatta, Tomohisa;Natsume, Tohru;Matsumoto, Kunio;Suga, Hiroaki
肝细胞生长因子（HGF）受体，也称为Met，是受体酪氨酸激酶家族的成员。Met-HGF相互作用调节涉及下游激酶如Akt和Erk的各种信号传导途径。Met活化通过由上述信号级联触发的多种生物学应答参与组织的伤口愈合。在这里，我们报告的发展，人工蛋氨酸活化二聚大环。我们通过RaPID（随机非标准肽集成发现）系统鉴定Met结合单体大环肽，并通过合理设计使相应单体二聚化。这些二聚大环化合物通过受体二聚化特异性地强烈激活Met信号传导途径，并在人细胞中诱导各种HGF样细胞反应，如分支形态发生。这项工作表明，我们的方法产生的二聚大环作为非蛋白质配体的细胞表面受体可以用于开发潜在的治疗与广泛的潜在应用。 肝细胞生长因子激活Met受体需要Met受体二聚化。在这里，作者鉴定了Met结合肽大环化合物，其作为化学交联的结果以二聚体形式诱导培养的人细胞中的Met受体二聚化和活化。
Hepatocyte growth factor (HGF) receptor, also known as Met, is a member of the receptor tyrosine kinase family. The Met–HGF interaction regulates various signalling pathways involving downstream kinases, such as Akt and Erk. Met activation is implicated in wound healing of tissues via multiple biological responses triggered by the above-mentioned signalling cascade. Here we report the development of artificial Met-activating dimeric macrocycles. We identify Met-binding monomeric macrocyclic peptides by means of the RaPID (random non-standard peptide integrated discovery) system, and dimerize the respective monomers through rational design. These dimeric macrocycles specifically and strongly activate Met signalling pathways through receptor dimerization and induce various HGF-like cellular responses, such as branching morphogenesis, in human cells. This work suggests our approach for generating dimeric macrocycles as non-protein ligands for cell surface receptors can be useful for developing potential therapeutics with a broad range of potential applications. Activation of the Met receptor by hepatocyte growth factor requires Met receptor dimerization. Here, the authors identify Met-binding peptide macrocycles that, in a dimeric form as a result of chemical crosslinking, induce Met receptor dimerization and activation in cultured human cells.
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影响因子：
4.3
作者：
Michieli, Paolo
通讯作者：
Michieli, Paolo
DOI：
10.3390/molecules180910514
发表时间：
2013-08-30
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Hipolito CJ;Tanaka Y;Katoh T;Nureki O;Suga H
通讯作者：
Suga H
DOI：
10.1152/ajplung.1996.270.6.l1031
发表时间：
1996-06-01
影响因子：
4.9
作者：
Ohmichi, H;Matsumoto, K;Nakamura, T
通讯作者：
Nakamura, T
影响因子：
7.4
作者：
Natsume, T;Yamauchi, Y;Isobe, T
通讯作者：
Isobe, T
影响因子：
56.9
作者：
BOTTARO, DP;RUBIN, JS;AARONSON, SA
通讯作者：
AARONSON, SA