7E50

Crystal structure of human microplasmin in complex with kazal-type inhibitor AaTI

7E50 の概要

• エントリーDOI: 10.2210/pdb7e50/pdb
• 分子名称: AAEL006007-PA, Plasminogen, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: plasmin, hydrolase
• 由来する生物種: Aedes aegypti (Yellowfever mosquito); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36832.94

構造登録者

Varsha, A.W.,Jobichen, C.,Mok, Y.K. (登録日: 2021-02-16, 公開日: 2022-02-16, 最終更新日: 2024-10-09)

主引用文献

Walvekar, V.A.,Ramesh, K.,Jobichen, C.,Kannan, M.,Sivaraman, J.,Kini, R.M.,Mok, Y.K.
Crystal structure of Aedes aegypti trypsin inhibitor in complex with mu-plasmin reveals role for scaffold stability in Kazal-type serine protease inhibitor.
Protein Sci., 31:470-484, 2022

PubMed Abstract: Kazal-type protease inhibitor specificity is believed to be determined by sequence of the reactive-site loop that make most, if not all, contacts with the serine protease. Here, we determined the complex crystal structure of Aedes aegypti trypsin inhibitor (AaTI) with μ-plasmin, and compared its reactivities with other Kazal-type inhibitors, infestin-1 and infestin-4. We show that the shortened 99-loop of plasmin creates an S2 pocket, which is filled by phenylalanine at the P2 position of the reactive-site loop of infestin-4. In contrast, AaTI and infestin-1 retain a proline at P2, rendering the S2 pocket unfilled, which leads to lower plasmin inhibitions. Furthermore, the protein scaffold of AaTI is unstable, due to an elongated Cys-V to Cys-VI region leading to a less compact hydrophobic core. Chimeric study shows that the stability of the scaffold can be modified by swapping of this Cys-V to Cys-VI region between AaTI and infestin-4. The scaffold instability causes steric clashing of the bulky P2 residue, leading to significantly reduced inhibition of plasmin by AaTI or infestin-4 chimera. Our findings suggest that surface loops of protease and scaffold stability of Kazal-type inhibitor are both necessary for specific protease inhibition, in addition to reactive site loop sequence. PDB ID code: 7E50.

PubMed: 34800067
DOI: 10.1002/pro.4245

実験手法

X-RAY DIFFRACTION (1.95 Å)