7THS

Macrocyclic plasmin inhibitor

7THS の概要

• エントリーDOI: 10.2210/pdb7ths/pdb
• 分子名称: Plasminogen, (6S,9R,20R,23S)-N-{[4-(aminomethyl)phenyl]methyl}-20-[(benzenesulfonyl)amino]-3,13,21-trioxo-2,6,9,14,22-pentaazatetracyclo[23.2.2.2~6,9~.2~15,18~]tritriaconta-1(27),15,17,25,28,30-hexaene-23-carboxamide, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: protease, inhibitor, blood clotting, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 57019.34

構造登録者

Guojie, W. (登録日: 2022-01-12, 公開日: 2023-01-18, 最終更新日: 2024-10-30)

主引用文献

Wiedemeyer, S.J.A.,Wu, G.,Pham, T.L.P.,Lang-Henkel, H.,Perez Urzua, B.,Whisstock, J.C.,Law, R.H.P.,Steinmetzer, T.
Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors.
Chemmedchem, 18:e202200632-e202200632, 2023

PubMed Abstract: Two series of macrocyclic plasmin inhibitors with a C-terminal benzylamine group were synthesized. The substitution of the N-terminal phenylsulfonyl group of a previously described inhibitor provided two analogues with sub-nanomolar inhibition constants. Both compounds possess a high selectivity against all other tested trypsin-like serine proteases. Furthermore, a new approach was used to selectively introduce asymmetric linker segments. Two of these compounds inhibit plasmin with K values close to 2 nM. For the first time, four crystal structures of these macrocyclic inhibitors could be determined in complex with a Ser195Ala microplasmin mutant. The macrocyclic core segment of the inhibitors binds to the open active site of plasmin without any steric hindrance. This binding mode is incompatible with other trypsin-like serine proteases containing a sterically demanding 99-hairpin loop. The crystal structures obtained experimentally explain the excellent selectivity of this inhibitor type as previously hypothesized.

PubMed: 36710259
DOI: 10.1002/cmdc.202200632

実験手法

X-RAY DIFFRACTION (1.8 Å)