STRUCTURES OF CATALYTIC DOMAINS OF BLOOD PROTEINS

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SEL2711 (C40H58O6Ng) is a combinatorially designed active site inhibitor of Factor Xa (Ki=3nM) and thrombin (Ki=45?M). The crystal of the complex of thrombin-hirugen has been used in a soaking experiment to obtain a ternary complex of thrombin-hirugen-SEL2711 for crystallographic analysis. The electron density map calculated from X-ray diffraction data indicates the absence of the two C-terminal residues of the inhibitor. This results from the cleavage of the SEL2711 and/or disorder of the residues which are located close to the surface of the protein. Therefore, the mass spectrometry (MALDI-MS) was used to support crystallographic data by a precise independent technique. Mass spectra of the complex and SEL2711 indicate that SEL2711 is cleaved by thrombin with the removal of only one C-terminal residue. The other residue is pointed out from the surface of the complex to the liquid intermolecular region and is disordered.