Abstract
Three-dimensional models of thrombin complexed with large fragments of the fibrinogen Aalpha and Bbeta chains are presented. The models are consistent with the results of recent mutagenesis studies of thrombin and with the information available on naturally occurring fibrinogen mutants. Thrombin recognizes fibrinogen with an extended binding surface, key elements of which are Tyr(76) in exosite I, located about 20 A away from the active site, and the aryl binding site located in close proximity to the catalytic triad. A highly conserved aromatic-Pro-aromatic triplet motif is identified in the primed site region of fibrinogen and other natural substrates of thrombin. The role of this triplet, based on the three-dimensional models, is to correctly orient the substrate for optimal bridge binding to exosite I and the active site. The three-dimensional models suggest a possible pattern of recognition by thrombin that applies generally to other natural substrates.
Highlights
Thrombin plays multiple functional roles in the blood by interacting with a variety of proteins
We report about three-dimensional models of thrombin complexed with large fragments of the A␣ and B chains of fibrinogen following a strategy recently used in the case of thrombin interaction with the G-protein-coupled receptors PAR1, PAR3, and PAR4 [3]
The three-dimensional models of thrombin bound to fragments of the human fibrinogen A␣ and B chains are consistent with available data on site-directed mutagenesis of thrombin and with the phenotype observed with several naturally occurring mutants of fibrinogen
Summary
Thrombin plays multiple functional roles in the blood by interacting with a variety of proteins. The thrombin-fibrinogen interaction has enjoyed renewed interest in recent years after the landmark solution of the crystal structure of fibrinogen derivatives (4 –7). Fragments of FpA covalently bound to the active site Ser195 of thrombin have been reported by x-ray crystallography [8, 9] and NMR spectroscopy [10] These studies have delineated the interactions made by FpA with the active site moiety of thrombin. Macromolecular bridge binding of fibrinogen to exosite I and the active site confers high specificity to the interaction and serves as a binding mode exploited by other natural substrates like the G-protein-coupled thrombin receptors [3]. In the case of the interaction of thrombin with the B chain of fibrinogen that is responsible for the release of FpB and protofibril polymerization, no structural information is currently available. The models are highly consistent with available data on site-directed and naturally occurring mutants of thrombin and fibrinogen
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