6lsq

Crystal structure of Echistatin, an RGD-containing short disintegrinCrystal structure of Echistatin, an RGD-containing short disintegrin

Structural highlights

6lsq is a 2 chain structure with sequence from Echis carinatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

VM2EA_ECHCS Potent inhibitor of ligand binding to the integrins alpha-V/beta-3 (ITGAV/ITGB3), alpha-5/beta-1 (ITGA5/ITGB1) and alpha-IIb/beta-3 (ITGA2B/ITGB3). Competition with fibrinogen for the RGD recognition sites on the alpha-IIb/beta-3 integrin (glyco-protein IIb/IIIa complex) results in the inhibition of platelet aggregation and other antithrombotic properties such as an ability to prevent coronary thrombosis in animal models. Is also a potent inhibitor of bone resorption. This results from the blocking of the interaction of alpha-V/beta-3 integrin on the surface of osteoclasts with bone extracellular matrix. In addition, interaction with alpha-V/beta-3 also inhibits adhesion of human umbilical vein endothelial cells (HUVEC) to immobilized vitronectin and fibronectin.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Echistatin (Ech) is a short disintegrin with a long (42)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 alphavbeta3, alphaIIbbeta3, alphavbeta5, and alpha5beta1. Mutagenesis of the C-terminus showed that the H44A mutant caused 2.5- and 4.4-fold increases in inhibiting alphaIIbbeta3 and alpha5beta1, and the K45A mutant caused a 2.6-fold decrease in inhibiting alphaIIbbeta3. 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.

Structural Insight into Integrin Recognition and Anticancer Activity of Echistatin.,Chen YC, Chang YT, Chen CY, Shiu JH, Cheng CH, Huang CH, Chen JF, Chuang WJ Toxins (Basel). 2020 Nov 9;12(11). pii: toxins12110709. doi:, 10.3390/toxins12110709. PMID:33182321^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Dennis MS, Henzel WJ, Pitti RM, Lipari MT, Napier MA, Deisher TA, Bunting S, Lazarus RA. Platelet glycoprotein IIb-IIIa protein antagonists from snake venoms: evidence for a family of platelet-aggregation inhibitors. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2471-5. PMID:2320569
↑ Gan ZR, Gould RJ, Jacobs JW, Friedman PA, Polokoff MA. Echistatin. A potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus. J Biol Chem. 1988 Dec 25;263(36):19827-32. PMID:3198653
↑ Marcinkiewicz C, Vijay-Kumar S, McLane MA, Niewiarowski S. Significance of RGD loop and C-terminal domain of echistatin for recognition of alphaIIb beta3 and alpha(v) beta3 integrins and expression of ligand-induced binding site. Blood. 1997 Aug 15;90(4):1565-75. PMID:9269775
↑ Chen YC, Chang YT, Chen CY, Shiu JH, Cheng CH, Huang CH, Chen JF, Chuang WJ. Structural Insight into Integrin Recognition and Anticancer Activity of Echistatin. Toxins (Basel). 2020 Nov 9;12(11):709. PMID:33182321 doi:10.3390/toxins12110709

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OCA

[1] Dennis MS, Henzel WJ, Pitti RM, Lipari MT, Napier MA, Deisher TA, Bunting S, Lazarus RA. Platelet glycoprotein IIb-IIIa protein antagonists from snake venoms: evidence for a family of platelet-aggregation inhibitors. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2471-5. PMID:2320569

[2] Gan ZR, Gould RJ, Jacobs JW, Friedman PA, Polokoff MA. Echistatin. A potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus. J Biol Chem. 1988 Dec 25;263(36):19827-32. PMID:3198653

[3] Marcinkiewicz C, Vijay-Kumar S, McLane MA, Niewiarowski S. Significance of RGD loop and C-terminal domain of echistatin for recognition of alphaIIb beta3 and alpha(v) beta3 integrins and expression of ligand-induced binding site. Blood. 1997 Aug 15;90(4):1565-75. PMID:9269775

[4] Chen YC, Chang YT, Chen CY, Shiu JH, Cheng CH, Huang CH, Chen JF, Chuang WJ. Structural Insight into Integrin Recognition and Anticancer Activity of Echistatin. Toxins (Basel). 2020 Nov 9;12(11):709. PMID:33182321 doi:10.3390/toxins12110709

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