6LSQ

Crystal structure of Echistatin, an RGD-containing short disintegrin

Summary for 6LSQ

• Entry DOI: 10.2210/pdb6lsq/pdb
• Descriptor: Disintegrin, SULFATE ION (3 entities in total)
• Functional Keywords: disintegrin, platelet aggregation inhibitor, blood clotting
• Biological source: Echis carinatus (Saw-scaled viper)
• Total number of polymer chains: 2
• Total formula weight: 11519.02

Authors

Chang, Y.T.,Chen, Y.C.,Chuang, W.J. (deposition date: 2020-01-19, release date: 2020-11-25, Last modification date: 2023-11-29)

Primary citation

Chen, Y.C.,Chang, Y.T.,Chen, C.Y.,Shiu, J.H.,Cheng, C.H.,Huang, C.H.,Chen, J.F.,Chuang, W.J.
Structural Insight into Integrin Recognition and Anticancer Activity of Echistatin.
Toxins, 12:-, 2020

PubMed Abstract: Echistatin (Ech) is a short disintegrin with a long NPHKGPAT 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 IC value of 103.2 nM and inhibited the migration of A375, U373MG, and Panc-1 tumor cells with IC 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.

PubMed: 33182321
DOI: 10.3390/toxins12110709

Experimental method

X-RAY DIFFRACTION (1.8 Å)