Abstract
The crystal structures of proflavin and 6-fluorotryptamine thrombin have been completed showing binding of both ligands at the active site S1 pocket. The structure of proflavin:thrombin was confirmatory, while the structure of 6-fluorotryptamine indicated a novel binding mode at the thrombin active site. Furthermore, speculation that the sodium atom identified in an extended solvent channel beneath the S1 pocket may play a role in binding of these ligands was investigated by direct proflavin titrations as well as chromogenic activity measurements as a function of sodium concentration at constant ionic strength. These results suggested a linkage between the sodium site and the S1 pocket. This observation could be due to a simple ionic interaction between Asp189 and the sodium ion or a more complicated structural rearrangement of the thrombin S1 pocket. Finally, the unique binding mode of 6-fluorotryptamine provides ideas toward the design of a neutrally charged thrombin inhibitor.
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Nienaber, V.L., Boxrud, P.D. & Berliner, L.J. Thrombin Inhibitor Design: X-Ray and Solution Studies Provide a Novel P1 Determinant. J Protein Chem 19, 327–333 (2000). https://doi.org/10.1023/A:1007055615190
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DOI: https://doi.org/10.1023/A:1007055615190