5LRJ

Crystal structure of the porcine carboxypeptidase B - Anabaenopeptin C complex

5LRJ の概要

• エントリーDOI: 10.2210/pdb5lrj/pdb
• 分子名称: Carboxypeptidase B, Anabaenopeptin C, ZINC ION, ... (4 entities in total)
• 機能のキーワード: drug discovery, natural compound, tafi inhibitor, anabaenopeptin, hydrolase
• 由来する生物種: Sus scrofa (Pig); 詳細
• 細胞内の位置: Secreted : P09955
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 106896.74

構造登録者

Schreuder, H.,Liesum, A.,Loenze, P. (登録日: 2016-08-19, 公開日: 2016-09-21, 最終更新日: 2024-11-13)

主引用文献

Schreuder, H.,Liesum, A.,Lonze, P.,Stump, H.,Hoffmann, H.,Schiell, M.,Kurz, M.,Toti, L.,Bauer, A.,Kallus, C.,Klemke-Jahn, C.,Czech, J.,Kramer, D.,Enke, H.,Niedermeyer, T.H.,Morrison, V.,Kumar, V.,Bronstrup, M.
Isolation, Co-Crystallization and Structure-Based Characterization of Anabaenopeptins as Highly Potent Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa).
Sci Rep, 6:32958-32958, 2016

PubMed Abstract: Mature thrombin activatable fibrinolysis inhibitor (TAFIa) is a carboxypeptidase that stabilizes fibrin clots by removing C-terminal arginines and lysines from partially degraded fibrin. Inhibition of TAFIa stimulates the degradation of fibrin clots and may help to prevent thrombosis. Applying a lead finding approach based on literature-mining, we discovered that anabaenopeptins, cyclic peptides produced by cyanobacteria, were potent inhibitors of TAFIa with IC50 values as low as 1.5 nM. We describe the isolation and structure elucidation of 20 anabaenopeptins, including 13 novel congeners, as well as their pronounced structure-activity relationships (SAR) with respect to inhibition of TAFIa. Crystal structures of the anabaenopeptins B, C and F bound to the surrogate protease carboxypeptidase B revealed the binding modes of these large (~850 Da) compounds in detail and explained the observed SAR, i.e. the strong dependence of the potency on a basic (Arg, Lys) exocyclic residue that addressed the S1' binding pocket, and a broad tolerance towards substitutions in the pentacyclic ring that acted as a plug of the active site.

PubMed: 27604544
DOI: 10.1038/srep32958

実験手法

X-RAY DIFFRACTION (2.2 Å)