1AVG

THROMBIN INHIBITOR FROM TRIATOMA PALLIDIPENNIS

Summary for 1AVG

• Entry DOI: 10.2210/pdb1avg/pdb
• Descriptor: THROMBIN, TRIABIN, ... (4 entities in total)
• Functional Keywords: bovine thrombin, thrombin inhibitor, complex (blood coagulation-inhibitor), complex (blood coagulation-inhibitor) complex, complex (blood coagulation/inhibitor)
• Biological source: Triatoma pallidipennis; More
• Cellular location: Secreted, extracellular space: P00735 P00735; Secreted: Q27049
• Total number of polymer chains: 3
• Total formula weight: 50604.32

Authors

Fuentes-Prior, P.,Huber, R.,Bode, W. (deposition date: 1997-09-16, release date: 1998-12-30, Last modification date: 2024-11-06)

Primary citation

Fuentes-Prior, P.,Noeske-Jungblut, C.,Donner, P.,Schleuning, W.D.,Huber, R.,Bode, W.
Structure of the thrombin complex with triabin, a lipocalin-like exosite-binding inhibitor derived from a triatomine bug.
Proc.Natl.Acad.Sci.USA, 94:11845-11850, 1997

PubMed Abstract: Triabin, a 142-residue protein from the saliva of the blood-sucking triatomine bug Triatoma pallidipennis, is a potent and selective thrombin inhibitor. Its stoichiometric complex with bovine alpha-thrombin was crystallized, and its crystal structure was solved by Patterson search methods and refined at 2.6-A resolution to an R value of 0.184. The analysis revealed that triabin is a compact one-domain molecule essentially consisting of an eight-stranded beta-barrel. The eight strands A to H are arranged in the order A-C-B-D-E-F-G-H, with the first four strands exhibiting a hitherto unobserved up-up-down-down topology. Except for the B-C inversion, the triabin fold exhibits the regular up-and-down topology of lipocalins. In contrast to the typical ligand-binding lipocalins, however, the triabin barrel encloses a hydrophobic core intersected by a unique salt-bridge cluster. Triabin interacts with thrombin exclusively via its fibrinogen-recognition exosite. Surprisingly, most of the interface interactions are hydrophobic. A prominent exception represents thrombin's Arg-77A side chain, which extends into a hydrophobic triabin pocket forming partially buried salt bridges with Glu-128 and Asp-135 of the inhibitor. The fully accessible active site of thrombin in this complex is in agreement with its retained hydrolytic activity toward small chromogenic substrates. Impairment of thrombin's fibrinogen converting activity or of its thrombomodulin-mediated protein C activation capacity upon triabin binding is explained by usage of overlapping interaction sites of fibrinogen, thrombomodulin, and triabin on thrombin. These data demonstrate that triabin inhibits thrombin via a novel and unique mechanism that might be of interest in the context of potential therapeutic applications.

PubMed: 9342325
DOI: 10.1073/pnas.94.22.11845

Experimental method

X-RAY DIFFRACTION (2.6 Å)