8RTN

Human thrombin in complex with a trivalent inhibitor

8RTN の概要

• エントリーDOI: 10.2210/pdb8rtn/pdb
• 分子名称: Prothrombin, Synthetic trivalent inhibitor, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: inhibitor, tyrosine-o-sulfate, blood clotting
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 145847.38

構造登録者

Ripoll-Rozada, J.,Maxwell, J.,Payne, R.J.,Pereira, P.J.B. (登録日: 2024-01-26, 公開日: 2025-02-12, 最終更新日: 2025-10-22)

主引用文献

Maxwell, J.W.C.,Ripoll-Rozada, J.,Mackay, A.S.,Alwis, I.,Ford, D.J.,Trought, C.B.J.,Santos, J.A.,Smythe, R.E.,Liu, J.S.T.,Zuccolotto, Z.,Schoenwaelder, S.M.,Jackson, S.P.,Pereira, P.J.B.,Payne, R.J.
Engineering ultrapotent trivalent anticoagulants through hybridisation of salivary peptides from multiple haematophagous organisms.
Chem Sci, 16:18660-18672, 2025

PubMed Abstract: Haematophagous organisms are a rich source of salivary anticoagulant polypeptides that exert their activity by blocking the catalytic site and one of two positively charged exosites on the host protease thrombin. Here, we describe a molecular engineering approach to hybridise post-translationally sulfated polypeptides from different blood-feeding organisms to enhance anticoagulant activity. This led to the discovery of a triply sulfated hybrid anticoagulant, XChimera, possessing fragments from flea, leech, and fly salivary polypeptides that exhibits femtomolar inhibitory activity against thrombin. The crystallographic structure of a complex of XChimera with thrombin shows that it displays a trivalent binding mode in which it simultaneously blocks three functional sites of the protease, the active site and exosites I and II. This trivalent chimera exhibited ultrapotent anticoagulant activity in a suite of clotting assays and was also shown to possess potent antithrombotic activity in a murine model of thrombosis.

PubMed: 40959396
DOI: 10.1039/d5sc04734j

実験手法

X-RAY DIFFRACTION (2.51 Å)