4E06

Anophelin from the malaria vector inhibits thrombin through a novel reverse-binding mechanism

4E06 の概要

• エントリーDOI: 10.2210/pdb4e06/pdb
• 関連するPDBエントリー: 4E05
• 分子名称: Thrombin, Salivary anti-thrombin peptide anophelin, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Anopheles albimanus (New world malaria mosquito); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 40663.65

構造登録者

Figueiredo, A.C.,de Sanctis, D.,Gutierrez-Gallego, R.,Cereija, T.B.,Macedo-Ribeiro, S.,Fuentes-Prior, P.,Pereira, P.J.B. (登録日: 2012-03-02, 公開日: 2012-12-05, 最終更新日: 2024-10-16)

主引用文献

Figueiredo, A.C.,de Sanctis, D.,Gutierrez-Gallego, R.,Cereija, T.B.,Macedo-Ribeiro, S.,Fuentes-Prior, P.,Pereira, P.J.
Unique thrombin inhibition mechanism by anophelin, an anticoagulant from the malaria vector.
Proc.Natl.Acad.Sci.USA, 109:E3649-E3658, 2012

PubMed Abstract: Anopheles mosquitoes are vectors of malaria, a potentially fatal blood disease affecting half a billion humans worldwide. These blood-feeding insects include in their antihemostatic arsenal a potent thrombin inhibitor, the flexible and cysteine-less anophelin. Here, we present a thorough structure-and-function analysis of thrombin inhibition by anophelin, including the 2.3-Å crystal structure of the human thrombin·anophelin complex. Anophelin residues 32-61 are well-defined by electron density, completely occupying the long cleft between the active site and exosite I. However, in striking contrast to substrates, the D50-R53 anophelin tetrapeptide occupies the active site cleft of the enzyme, whereas the upstream residues A35-P45 shield the regulatory exosite I, defining a unique reverse-binding mode of an inhibitor to the target proteinase. The extensive interactions established, the disruption of thrombin's active site charge-relay system, and the insertion of residue R53 into the proteinase S(1) pocket in an orientation opposed to productive substrates explain anophelin's remarkable specificity and resistance to proteolysis by thrombin. Complementary biophysical and functional characterization of point mutants and truncated versions of anophelin unambiguously establish the molecular mechanism of action of this family of serine proteinase inhibitors (I77). These findings have implications for the design of novel antithrombotics.

PubMed: 23223529
DOI: 10.1073/pnas.1211614109

実験手法

X-RAY DIFFRACTION (3.196 Å)