X-RAY STRUCTURE OF ACTIVE SITE-INHIBITED CLOTTING FACTOR XA - IMPLICATIONS FOR DRUG DESIGN AND SUBSTRATE RECOGNITION

The 3.0-Angstrom resolution x-ray structure of human des-Gla-coagulati on factor Xa (fXa) has been determined in complex with the synthetic i nhibitor DX-9065a. The binding geometry is characterized primarily by two interaction sites: the naphthamidine group is fixed in the S1 pock et by a typical salt bridge to Asp-189, while the pyrrolidine ring bin ds in the unique aryl-binding site (S4) of fXa. Unlike the large major ity of inhibitor complexes with serine proteinases, Gly-216 (S3) does not contribute to hydrogen bond formation. In contrast to typical thro mbin binding modes, the S2 site of fXa cannot be used by DX-9065a sinc e it is blocked by Tyr-99, and the aryl-binding site (S4) of fXa is li ned by carbonyl oxygen atoms that can accommodate positive charges. Th is has implications for natural substrate recognition as well as for d rug design.