8RTN
Human thrombin in complex with a trivalent inhibitor
Summary for 8RTN
| Entry DOI | 10.2210/pdb8rtn/pdb |
| Descriptor | Prothrombin, Synthetic trivalent inhibitor, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total) |
| Functional Keywords | inhibitor, tyrosine-o-sulfate, blood clotting |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 145847.38 |
| Authors | Ripoll-Rozada, J.,Maxwell, J.,Payne, R.J.,Pereira, P.J.B. (deposition date: 2024-01-26, release date: 2025-02-12, Last modification date: 2025-10-22) |
| Primary citation | 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 Cited by 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: 40959396DOI: 10.1039/d5sc04734j PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.51 Å) |
Structure validation
Download full validation report
