Sulfotyrosine-Mediated Recognition of Human Thrombin by a Tsetse Fly Anticoagulant Mimics Physiological Substrates

• Tipo: Artigo em Revista Científica Internacional
• Data: 2021

Autores

Calisto, BM (Autor) Outra; Ripoll Rozada, J (Autor) Outra; Dowman, LJ (Autor) Outra; Franck, C (Autor) Outra; Agten, SM (Autor) Outra; Parker, BL (Autor) Outra; Veloso, RC (Autor) Outra; Nuno Vale (Autor) FMUP; Paula Gomes (Autor) FCUP; de Sanctis, D (Autor) Outra; Payne, RJ (Autor) Outra; Pereira, PJB (Autor) Outra

Revista

Título: Cell Chemical Biology

Vol. 28

Páginas: 26-+

ISSN: 2451-9448

Editora: Elsevier

Indexação

ISI Web of Knowledge - 14 Citações

Scopus - 14 Citações

Outras Informações

ID Authenticus: P-00S-YN2

DOI: 10.1016/j.chembiol.2020.10.002

Abstract (EN): Despite possessing only 32 residues, the tsetse thrombin inhibitor (TTI) is among the most potent anticoagulants described, with sub-picomolar inhibitory activity against thrombin. Unexpectedly, TTI isolated from the fly is 2000-fold more active and 180 Da heavier than synthetic and recombinant variants. We predicted the presence of a tyrosine O-sulfate post-translational modification of TTI, prompting us to investigate the effect of the modification on anticoagulant activity. A combination of chemical synthesis and functional assays was used to reveal that sulfation significantly improved the inhibitory activity of TTI against thrombin. Using X-ray crystallography, we show that the N-terminal sulfated segment of TTI binds the basic exosite II of thrombin, establishing interactions similar to those of physiologic substrates, while the C-terminal segment abolishes the catalytic activity of thrombin. This non-canonical mode of inhibition, coupled with its potency and small size, makes TTI an attractive scaffold for the design of novel antithrombotics.

Idioma: Inglês

Tipo (Avaliação Docente): Divulgação

Nº de páginas: 16