5GIM

Crystal structure of thrombin-avathrin complex

5GIM の概要

• エントリーDOI: 10.2210/pdb5gim/pdb
• 分子名称: Thrombin light chain, thrombin heavy chain, N-terminal peptide from Putative uncharacterized protein avahiru, ... (5 entities in total)
• 機能のキーワード: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Secreted, extracellular space: P00734
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 37037.17

構造登録者

Kini, R.M.,Koh, C.Y.,Iyer, J.K.,Swaminathan, K. (登録日: 2016-06-24, 公開日: 2017-05-03, 最終更新日: 2024-10-16)

主引用文献

Iyer, J.K.,Koh, C.Y.,Kazimirova, M.,Roller, L.,Jobichen, C.,Swaminathan, K.,Mizuguchi, J.,Iwanaga, S.,Nuttall, P.A.,Chan, M.Y.,Kini, R.M.
Avathrin: a novel thrombin inhibitor derived from a multicopy precursor in the salivary glands of the ixodid tick, Amblyomma variegatum.
FASEB J., 31:2981-2995, 2017

PubMed Abstract: Tick saliva is a rich source of antihemostatic compounds. We amplified a cDNA from the salivary glands of the tropical bont tick () using primers based on the variegin sequence, which we previously identified as a novel thrombin inhibitor from the same tick species. The transcript encodes a precursor protein comprising a signal peptide and 5 repeats of variegin-like sequences that could be processed into multiple short peptides. These peptides share 31 to 34% identity with variegin. Here, we structurally and functionally characterized one of these peptides named "avathrin." Avathrin is a fast, tight binding competitive inhibitor with an affinity of 545 pM for thrombin and is 4 orders of magnitude more selective towards thrombin than to the other serine proteases of the coagulation cascade. The crystal structure of thrombin-avathrin complex at 2.09 Å revealed that avathrin interacts with the thrombin active site and exosite-I. Although avathrin is cleaved by thrombin, the C-terminal cleavage product continues to exert prolonged inhibition. Avathrin is more potent than hirulog-1 in a murine carotid artery thrombosis model. Such precursor proteins that could be processed into multiple thrombin inhibiting peptides appear to be widespread among Amblyomminae, providing an enormous library of molecules for development as potent antithrombotics.-Iyer, J. K., Koh, C. Y., Kazimirova, M., Roller, L., Jobichen, C., Swaminathan, K., Mizuguchi, J., Iwanaga, S., Nuttall, P. A., Chan, M. Y., Kini, R. M. Avathrin: a novel thrombin inhibitor derived from a multicopy precursor in the salivary glands of the ixodid tick, .

PubMed: 28363953
DOI: 10.1096/fj.201601216R

実験手法

X-RAY DIFFRACTION (2.09 Å)