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

Journal Article · Tue Apr 01 04:00:00 EDT 2008 · Acta Crystallographica. Section D: Biological Crystallography

DOI:https://doi.org/10.1107/S0907444908002370· OSTI ID:22347995

Moiseeva, Natalia ^[1]; Bau, Robert ^[2]; Swenson, Stephen D.; Markland, Jr, Francis S. ^[3]; Choe, Jun-Yong ^[4]; Liu, Zhi-Jie ^[5]; Allaire, Marc ^[1]

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1. National Synchrotron Light Source, Brookhaven National Laboratory, Building 725D, Upton, NY 11973 (United States)
2. Chemistry Department, University of Southern California, Los Angeles, CA 90089 (United States)
3. Department of Biochemistry and Molecular Biology and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 (United States)
4. Division of Chemistry and Chemical Engineering, Howard Hughes Medical Institute/California Institute of Technology, Pasadena, CA 91125 (United States)
5. Departments of Biochemistry and Molecular Biology and Chemistry, University of Georgia, Athens, GA 30602 (United States)

Two acostatin heterodimers interact together to form an αββα tetramer. 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{sub work} and R{sub 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.

• OSTI ID: 22347995
• Journal Information: Acta Crystallographica. Section D: Biological Crystallography, Journal Name: Acta Crystallographica. Section D: Biological Crystallography Journal Issue: Pt 4 Vol. 64; ISSN ABCRE6; ISSN 0907-4449
• Country of Publication: Denmark
• Language: English

Related Subjects

75 CONDENSED MATTER PHYSICS
SUPERCONDUCTIVITY AND SUPERFLUIDITY
CHAINS
CRYSTALS
DIMERS
FLEXIBILITY
IN VIVO
INTERACTIONS
LENGTH
PROTEINS
RESOLUTION
SHEETS