Purification, crystallization and preliminary X-ray analysis of the disintegrin contortrostatin from<i>Agkistrodon contortrix contortrix</i>snake venom

Moiseeva, Natalia; Swenson, Stephen D.; Markland, Francis S.; Bau, Robert

doi:10.1107/s0907444902011204

Cited by 9 publications

(6 citation statements)

References 11 publications

(12 reference statements)

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“…Two disintegrins (contortrostatin and acostatin) have been isolated from A. contortrix [28, 29, 30]. Contortrostin is a homodimer disintegrin whereas acostatin is a heterodimer disintegrin; both containing a RGD motif in each chain [29, 30].…”

Section: Discussionmentioning

confidence: 99%

The characterization of trans-pecos copperhead (Agkistrodon contortrix pictigaster) venom and isolation of two new dimeric disintegrins

et al. 2016

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The vast amounts of toxins within the venom of snakes, while known to cause medical emergencies, display various biological functions. Trans-pecos copperhead (Agkistrodon contortrix pictigaster) crude venom separated by cation-exchange chromatography showed several fractions with fibrinolytic, hemorrhagic, gelatinase and platelet activities. Venom fractions 1, 2, 4, 5, and 12-17 contained fibrinolytic activity. Venom fractions 1, 2, 5 and 12-14 had hemorrhagic activity. Fractions 1, 2, 12, 13 and 17 contained gelatinase activity. Reverse-Phase C18 High Performance Liquid Chromatography was also used to purify and isolated disintegrins from this venom. Anti-platelet aggregation activity of the C18 fractions collected and performed on whole human blood showed that they inhibited platelet aggregation in presence of several agonists. Results from both SDS-PAGE and N-terminal sequencing determined that pictistatin 1 obtained from the Trans-Pecos copperhead venom was a dimeric disintegrin, and pictistatin 2 was a heterodimeric disintegrin. The molecules with anti-platelet activity could be considered in the development of more effective drugs, for numerous blood-related diseases such as stroke, heart attacks, thrombosis, and other medical conditions. In this study, we are presenting the first report of the purification, isolation, and partial characterization of two new dimeric disintegrins isolated from the venom of trans-pecos copperhead.

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Section: Discussionmentioning

confidence: 99%

The characterization of trans-pecos copperhead (Agkistrodon contortrix pictigaster) venom and isolation of two new dimeric disintegrins

et al. 2016

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“…The most striking feature is the disulfide bonds around the RGD sequence, which is similar enough to define an "RGD-containing loop" in each protein, the formation of which may be important to their biological activity, especially their potency and selectivity. NMR studies of this loop in snake venom proteins, including kistrin [238][239][240], flavoridin [241], echistatin [242][243][244][245], albolabrin [246], decorsin [247], dendroaspin [248,249], and salmosin [250] as well as a crystal structure studies of the applaggin [251], schistatin [252,253], acostatin [254], contortrostatin [255], trimstatin [256], and an XCD (X denotes any amino acid residue) motif-containing jararhagin [257], show that the RGD/XCD sequence is invariably presented at the apex of a β-turn (Fig. 5).…”

Section: Structural Features Of Rgd-containing Snake Venom Toxinsmentioning

confidence: 99%

Integrins in Drug Targeting-RGD Templates in Toxins

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Lu²,

Scully³

et al. 2006

CPD

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Integrins are a family of heterodimeric receptors, which modulate many cellular processes including: growth, death (apoptosis), adhesion, migration, and invasion by activating several signaling pathways. Integrin-binding RGD (arginine-glycine-aspartic acid) is found in several important extracellular matrix proteins which serve as adhesive integrin ligands. The RGD motif has also been found in many toxins from snake venom and other sources that specifically inhibit integrin binding function and serve as potent integrin antagonists, particularly of platelet aggregation and integrin-mediated cell adhesion. Many of these proteins have potential as therapeutic agents which can target integrins directly. Structural and functional studies of several RGD-containing toxins suggest that the inhibitory potency of these proteins lies in subtle positional requirements of the tripeptide RGD at the tip of a flexible loop, a structural feature for binding to integrins. In addition, amino acid residues in this loop in close vicinity to the RGD-motif determine the integrin-binding specificity and selectivity. This review will present a review of integrin structure and function, and of disintegrin structural features responsible for their activity as antagonists of integrin function. The use of integrins in drug targeting and integrins as targets for drug delivery by using the RGD as a template structure will also be discussed.

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“…Contortrostatin (Mr 13,500) is a homodimeric disintegrin isolated from venom of the southern copperhead snake (Trikha et al, 1994a); each of the monomeric chains contains 65 amino acids (Zhou et al, 2000a). Each chain of the disulfide rich homodimer possesses an RGD motif at the tip of a flexible loop stabilized by disulfide bonds (McLane et al, 1996;Moiseeva et al, 2002). Interaction of CN with tumor cells is primarily modulated by the RGD motif (Trikha et al, 1994a).…”

Section: Introductionmentioning

confidence: 99%

A Snake Venom Disintegrin With Potent Antitumor and Antiangiogenic Activity

et al. 2005

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In this report we describe an effective method for delivery of a novel snake venom disintegrin, contortrostatin (CN), in an orthotopic, xenograft model of human mammary cancer in immunodeficient mice. Contortrostatin (Mr 13,500) is a homodimeric disintegrin isolated from venom of the southern copperhead snake. Contortrostatin possesses two RGD sites, one in each chain, which modulate its interaction with integrins on tumor cells and angiogenic vascular endothelial cells. Although our laboratory has previously described the antitumor activity of CN in a mouse model of human mammary cancer, the method of delivery, daily intratumor injection, was not translatable to clinical application. We now describe a clinically relevant method of administering CN, liposomal delivery (LCN). A unique liposomal system has been designed for intravenous (IV) administration of a biologically active protein with full retention of biological activity. Pharmacokinetics, biodistribution, platelet reactivity, and immunogenicity of LCN were examined and compared with similar characteristics of native, unencapsulated CN. There are several advantages to liposomal delivery of CN: (i) LCN has a significantly prolonged circulatory half-life compared to native CN; (ii) LCN is passively accumulated in the tumor; (iii) LCN has no platelet reactivity; and (iv) LCN is not recognized by the immune system. We have previously demonstrated that antiangiogenic Generated by TechBooks Automated Layout System 114 F. S. Markland et al. activity is an important component of CN's mechanism of antitumor action. In the present communication we demonstrate that IV delivery of LCN leads to potent antitumor and antiangiogenic activity in the orthotopic, xenograft human mammary cancer model.

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Purification, crystallization and preliminary X-ray analysis of the disintegrin contortrostatin fromAgkistrodon contortrix contortrixsnake venom

Cited by 9 publications

References 11 publications

The characterization of trans-pecos copperhead (Agkistrodon contortrix pictigaster) venom and isolation of two new dimeric disintegrins

The characterization of trans-pecos copperhead (Agkistrodon contortrix pictigaster) venom and isolation of two new dimeric disintegrins

Integrins in Drug Targeting-RGD Templates in Toxins

A Snake Venom Disintegrin With Potent Antitumor and Antiangiogenic Activity

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