Structural Insight into Integrin Recognition and Anticancer Activity of Echistatin

Yi Chun Chen, Yao Tsung Chang, Chiu Yueh Chen, Jia Hau Shiu, Chun Ho Cheng, Chun Hao Huang, Ju Fei Chen, Woei Jer Chuang

Research output: Contribution to journalArticlepeer-review

Abstract

Echistatin (Ech) is a short disintegrin with a long 42NPHKGPAT C-terminal tail. We determined the 3-D structure of Ech by X-ray crystallography. Superimposition of the structures of chains A and B showed conformational differences in their RGD loops and C-termini. The chain A structure is consistent with our NMR analysis that the GPAT residues of the C-terminus cannot be observed due to high flexibility. The hydrogen bond patterns of the RGD loop and between the RGD loop and C-terminus in Ech were the same as those of the corresponding residues in medium disintegrins. The mutant with C-terminal HKGPAT truncation caused 6.4-, 7.0-, 11.7-, and 18.6-fold decreases in inhibiting integrins αvβ3, αIIbβ3, αvβ5, and α5β1. Mutagenesis of the C-terminus showed that the H44A mutant caused 2.5- and 4.4-fold increases in inhibiting αIIbβ3 and α5β1, and the K45A mutant caused a 2.6-fold decrease in inhibiting αIIbβ3. We found that Ech inhibited VEGF-induced HUVEC proliferation with an IC50 value of 103.2 nM and inhibited the migration of A375, U373MG, and Panc-1 tumor cells with IC50 values of 1.5, 5.7, and 154.5 nM. These findings suggest that Ech is a potential anticancer agent, and its C-terminal region can be optimized to improve its anticancer activity.

Original languageEnglish
JournalToxins
Volume12
Issue number11
DOIs
Publication statusPublished - 2020 Nov 9

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Health, Toxicology and Mutagenesis

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