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

Moiseeva, Natalia and Bau, Robert and Swenson, Stephen D. and Markland, Francis S. and Choe, Jun-Yong and Liu, Zhi-Jie and Allaire, Marc (2008) Structure of acostatin, a dimeric disintegrin from Southern copperhead (Agkistrodon contortrix contortrix), at 1.7 Å resolution. Acta Crystallographica Section D: Biological Crystallography, 64 (4). pp. 466-470. ISSN 0907-4449. PMCID PMC2631110.

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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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Additional Information:© 2008 International Union of Crystallography. Received 5 November 2007. Accepted 22 January 2008. We thank the SSRL, the ALS and their staff for providing access to the beamline facility. This work was supported in part by funds provided to MA by the Department of Energy under contract No. DEAC02-98CH10866, the National Institutes of Health/National Institute of General Medical Sciences under agreement Y1 GM-0080-03 and the Brookhaven National Laboratory/Laboratory Directed Research and Development Program. RB acknowledges partial support from the National Science Foundation (grant CHE-98-16294) as well as from the Zumberge Research Innovation Fund of the University of Southern California.
Funding AgencyGrant Number
Department of Energy (DOE)DE-AC02-98CH10866
NIHY1 GM-0080-03
Brookhaven National LaboratoryUNSPECIFIED
University of Southern CaliforniaUNSPECIFIED
Subject Keywords:disintegrins; acostatin; tetramer
Issue or Number:4
PubMed Central ID:PMC2631110
Record Number:CaltechAUTHORS:20170316-073531299
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Official Citation:Moiseeva, N., Bau, R., Swenson, S. D., Markland, F. S., Choe, J.-Y., Liu, Z.-J. and Allaire, M. (2008), Structure of acostatin, a dimeric disintegrin from Southern copperhead (Agkistrodon contortrix contortrix), at 1.7 Å resolution. Acta Crystallographica Section D, 64: 466–470. doi: 10.1107/S0907444908002370
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75172
Deposited By: Ruth Sustaita
Deposited On:16 Mar 2017 16:27
Last Modified:21 May 2020 22:31

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