9AZK

Macrocyclic inhibitors targeting the prime site of the fibrinolytic serine protease plasmin

これはPDB形式変換不可エントリーです。

9AZK の概要

• エントリーDOI: 10.2210/pdb9azk/pdb
• 分子名称: Plasminogen, (1r,4S)-4-(aminomethyl)-N-[(24S)-5-methyl-8,11,16,23-tetraoxo-7,10,15,22-tetraazatetracyclo[24.2.2.2~18,21~.1~2,6~]tritriaconta-1(28),2(33),3,5,18,20,26,29,31-nonaen-24-yl]cyclohexane-1-carboxamide (3 entities in total)
• 機能のキーワード: protease inhibitor, fibrinolysis, 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: 6
• 化学式量合計: 168013.27

構造登録者

Guojie, W. (登録日: 2024-03-11, 公開日: 2024-10-30, 最終更新日: 2025-05-21)

主引用文献

Wiedemeyer, S.J.A.,Wu, G.,Lang-Henkel, H.,Whisstock, J.C.,Law, R.H.P.,Steinmetzer, T.
Macrocyclic Inhibitors Targeting the Prime Site of the Fibrinolytic Serine Protease Plasmin.
Chemmedchem, 19:e202400360-e202400360, 2024

PubMed Abstract: Two series of macrocyclic inhibitors addressing the S1 pocket and the prime site of the fibrinolytic serine protease plasmin have been developed. In the first series, a P1 tranexamoyl residue was coupled to 4-aminophenylalanine in P1' position, which provided moderately potent inhibitors with inhibition constants around 1 μM. In the second series, a substituted biphenylalanine was incorporated as P1' residue leading to approximately 1000-fold stronger plasmin inhibitors, the best compounds possess subnanomolar inhibition constants. The most effective compounds already exhibit a certain selectivity as plasmin inhibitors compared to other trypsin-like serine proteases such as trypsin, plasma kallikrein, thrombin, activated protein Ca, as well as factors XIa and Xa. For inhibitor 28 of the second series, the co-crystal structure in complex with a Ser195Ala microplasmin mutant revealed that the P2' residue adopts multiple conformations. Most polar contacts to plasmin and surrounding water molecules are mediated through the P1 tranexamoyl residue, whereas the bound conformation of the macrocycle is mainly stabilized by two intramolecular hydrogen bonds.

PubMed: 39118493
DOI: 10.1002/cmdc.202400360

実験手法

X-RAY DIFFRACTION (2.1 Å)