Structure of Acostatin, a Dimeric Disintegrin From Southern Copperhead (Agkistrodon Contortrix Contortrix), at 1.7 Angstrom Resolution

Journal Article · Tue May 26 04:00:00 EDT 2009 · Acta Crystallogr.D Biol.Crystallogr.64:466,2008

OSTI ID:953620

Moiseeva, N; Bau, R; Swenson, S D; Marklund, F S; Jr,; Choe, J -Y; Liu, Z -J; Allaire, M

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 {alpha}{beta} 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 {angstrom} 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 {beta}-sheets, each of which is formed by a pair of antiparallel {beta}-strands connected by {beta}-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 {alpha}{beta}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 {alpha}{beta}{beta}{alpha} acostatin tetramer. Further experiments are required to identify whether the {alpha}{beta}{beta}{alpha} acostatin complex plays a functional role in vivo.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 953620
• Report Number(s): SLAC-REPRINT-2009-263
• Journal Information: Acta Crystallogr.D Biol.Crystallogr.64:466,2008, Journal Name: Acta Crystallogr.D Biol.Crystallogr.64:466,2008 Journal Issue: 4 Vol. 64; ISSN 0907-4449
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
CRYSTALLOGRAPHY
CRYSTALS
DATA
DIMERS
DISULFIDES
FLEXIBILITY
FUNCTIONALS
IN VIVO
INTERACTIONS
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OTHER
BIO
PROTEINS
RANGE
RESOLUTION
UNITS
VENOMS