Journal:JBSD:14

Traditional Chinese medicine as dual guardians against hypertension and cancer?

Weng Ieong Tou, Calvin Yu-Chian Chen ^[1]

Molecular Tour
Src kinase functions as a signal protein and is implicated in various diseases. The carboxyl terminal of Src kinase is important in regulating conformation and activity of Src. Src protein is locked as an inward folding conformation through binding between the phosphorylated Tyr527 and the SH2 domain under normal inactive conditions. Src is activated when dephosphorylation of Tyr527 and phosphorylation of Tyr419 occurs. From N-terminal to C-terminal, Src is composed of a smaller amino-terminal lobe (residues 270–340; colored in violet) which binds adenosine triphosphate (ATP) and a larger carboxyl-terminal lobe (residues 345–523; colored in green) which binds with substrates. The ATP binding site is also partially located in the larger lobe. By regulating the alpha-helix structure, the large lobe can move toward or away from the small lobe, opening or closing the cleft between the two lobes. The Src catalytic site is located within the cleft. An open conformation allows the entrance of ATP into the cleft and exit of adenosine diphosphate (ADP) from the cleft. Drugs that can either interact with the residues (404–432) on the activation loop or inhibit the activation loop from moving away and opening the cleft as a result of Tyr419 phosphorylation can effectively inhibit Src activity. In this in vivo study, Angeliferulate and HMID have multiple stable interactions with the two Src cleft loops while simultaneously interacting with Asp407, hindering the activation loop from activation. Considering the aforementioned interactions with Src and high affinity with EGFR, HER2, and HSP90, we suggest that Angeliferulate and HMID which both originate from the TCM Angelica sinensis may have potential as multi-targeting drug leads.