Structure of acostatin, a dimeric disintegrin from Southern copperhead (Agkistrodon contortrix contortrix), at 1.7 Å resolution

National Synchrotron Light Source, Brookhaven National Laboratory, Building 725D, Upton, NY 11973, USA.
Acta Crystallographica Section D Biological Crystallography (Impact Factor: 2.67). 05/2008; 64(Pt 4):466-70. DOI: 10.1107/S0907444908002370
Source: PubMed


Disintegrins are a family of small (4–14 kDa) proteins that bind to another class of proteins, integrins. Therefore, as integrin inhibitors, they can be exploited as anticancer and antiplatelet agents. Acostatin, an αβ heterodimeric disintegrin, has been isolated from the venom of Southern copperhead (Agkistrodon contortrix contortrix). The three-dimensional structure of acostatin has been determined by macromolecular crystallography using the molecular-replacement method. The asymmetric unit of the acostatin crystals consists of two heterodimers. The structure has been refined to an R
work and R
free of 18.6% and 21.5%, respectively, using all data in the 20–1.7 Å resolution range. The structure of all subunits is similar and is well ordered into N-terminal and C-­terminal clusters with four intramolecular disulfide bonds. The overall fold consists of short β-sheets, each of which is formed by a pair of antiparallel β-strands connected by β-turns and flexible loops of different lengths. Conformational flexibility is found in the RGD loops and in the C-terminal segment. The interaction of two N-terminal clusters via two intermolecular disulfide bridges anchors the αβ chains of the acostatin dimers. The C-terminal clusters of the heterodimer project in opposite directions and form a larger angle between them in comparison with other dimeric disintegrins. Extensive interactions are observed between two heterodimers, revealing an αββα acostatin tetramer. Further experiments are required to identify whether the αββα acostatin complex plays a functional role in vivo.

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    • "These small polypeptides hold a significant translational potential as anti-cancer agents based on their anti-angiogenic and anti-metastatic effects demonstrated in various experimental settings [20], [21], [22]. The integrin-binding activity of disintegrins depends on the appropriate pairing of several cysteine residues responsible for the disintegrin fold, a mobile 11-amino acid loop protruding from the polypeptide core displaying a tri-peptide motif, usually RGD (Arg-Gly-Asp), that is conserved in many disintegrins [23], [24]. Although these molecules naturally evolved to efficiently bind to the activated platelet-specific integrin αIIbβ3, thus disrupting the process of platelet aggregation (the final step in blood clotting), most purified snake venom disintegrins are rather promiscuous in that they bind to several β1, β3 or β5 integrin members, albeit with different affinities and selectivity [25]. "
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