1T1F

Crystal Structure of Native Antithrombin in its Monomeric Form

1T1F の概要

• エントリーDOI: 10.2210/pdb1t1f/pdb
• 分子名称: Antithrombin-III, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: serine-cysteine proteinase inhibitor; thrombin; human; x-ray crystallography, blood clotting
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted, extracellular space: P01008
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 154520.50

構造登録者

Johnson, D.J.D.,Huntington, J.A. (登録日: 2004-04-16, 公開日: 2005-10-04, 最終更新日: 2024-10-30)

主引用文献

Johnson, D.J.D.,Langdown, J.,Li, W.,Luis, S.A.,Baglin, T.P.,Huntington, J.A.
Crystal structure of monomeric native antithrombin reveals a novel reactive center loop conformation
J.Biol.Chem., 281:35478-35486, 2006

PubMed Abstract: The poor inhibitory activity of circulating antithrombin (AT) is critical to the formation of blood clots at sites of vascular damage. AT becomes an efficient inhibitor of the coagulation proteases only after binding to a specific heparin pentasaccharide, which alters the conformation of the reactive center loop (RCL). The molecular basis of this activation event lies at the heart of the regulation of hemostasis and accounts for the anticoagulant properties of the low molecular weight heparins. Although several structures of AT have been solved, the conformation of the RCL in native AT remains unknown because of the obligate crystal contact between the RCL of native AT and its latent counterpart. Here we report the crystallographic structure of a variant of AT in its monomeric native state. The RCL shifted approximately 20 A, and a salt bridge was observed between the P1 residue (Arg-393) and Glu-237. This contact explains the effect of mutations at the P1 position on the affinity of AT for heparin and also the properties of AT-Truro (E237K). The relevance of the observed conformation was verified through mutagenesis studies and by solving structures of the same variant in different crystal forms. We conclude that the poor inhibitory activity of the circulating form of AT is partially conferred by intramolecular contacts that restrain the RCL, orient the P1 residue away from attacking proteases, and additionally block the exosite utilized in protease recognition.

PubMed: 16973611
DOI: 10.1074/jbc.M607204200

実験手法

X-RAY DIFFRACTION (2.75 Å)