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Document Page 287 cal in sequence with the exception of the Glu 46 Lys switch, suggests this residue is of minor importance. Therefore, the potency of 50cl (within a factor of 3) is consistent with r-TFPI-II. On the other hand, the incorporation of Val for Lys at position 34 leads to a dramatic increase in potency (˜100 fold; cf. 4c10 and 4c2 with 50c1). From cluster 2 above this suggests the importance of P5, P'2,P'4 for potency. The changes in wild type BPTI that result in a potent Factor Xa inhibitor are Lys 15 rarrow.gif Arg 15, Arg 17, rarrow.gif Tyr 17, and Arg 39 rarrow.gif Leu 39. B. Random Mutagenesis 11Libraries of mutant BPTI were created by inserting mutagenic cassettes in the BPTI gene of filamentous phage PIII coat proteins [76]. These libraries produced large numbers of mutants (~10 6) with randomized amino acids in positions 11, 13, 16, 17, 18, 19, 20, 34, and 39. The mutants were panned against Factor Xa, which was affixed to a solid support by a nonneutralizing antibody and the most potent inhibitors were separately expressed as soluble proteins. By this process it was possible to determine consensus sequences at the reactive sites and to define the pharmacophore requirements of inhibitors of Factor Xa in both a functional and conformational sense from the P4 to the P5 positions. Inhibitor amino acid preferences from both site directed and random mutagenesis studies are shown in Table 6. VIII. Positional Requirements of Factor Xa Inhibitors (Table 6) Examination of models of BPTI-mutants bound to Factor Xa show the L-amino acids in the P3 position project into solvent. In the Factor Xa cleavage sites in thrombin these residues are polar and acidic (Glu, Asp); they are polar and basic in antistasin (Arg), and polar and neutral in Ecotin (Ser). The exception is TFPI- II, with this position occupied by Ile. The BPTI random mutant results are consistent with the TFPI-II case and show a preference for aliphatics or aromatics in this position. There is a hydrophobic pocket in the enzyme, formed by Trp 215, Tyr 99, and Phe 174, that would be accessible to a D-residue in this position. The accessibility of the S2 pocket of the enzyme by P2 groups would be expected to be influenced by the orientation of Tyr 99. As the x-ray structure shows its position this residue puts severe limitations on the size of the P2 group. Consistent with this is the observation that Gly is the sole residue in the FXa:thrombin cleavage sites. Little information is available from the BPTI mutants, TFPI-II, or antistasin, which all have a structural requirement for Cys at this position. Synthetic compounds show, however, that in potent inhibitors large bulky aromatics are, in fact, allowed at this position, a situation that requires Tyr 99 to move out of the way [75]. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_287.html [4/5/2004 5:14:31 PM]
Document Page 288 Additionally, the binding of BPTI mutants also requires Tyr 99 to move because of potential severe interactions with the Cys 14–Cys 38 bridge of the BPTI mutants. While larger groups can be accommodated, structural requirements are fairly rigid in agreement with the limited mobility expected of the Tyr 99. The apparent requirement for a P2-Gly in the larger substrates may suggest that in these cases extended binding occurs that does not permit movement of Tyr 99. In the P1 position, as expected, a basic group is preferred. Interestingly, of the two naturally occuring basic amino acids, arginine is preferred over lysine. This is seen in both the BPTI mutants as well as the Arg rarrow.gif Lys switch in antistasin. This may be due to Ala 190 in the S1 pocket of FXa, which cannot orient and stabilize the BPTI lysine analog as Ser 190 does in trypsin. An interesting exception to the need for a basic group is in Ecotin where a methionine occupies this site. The x-ray of Ecotin with trypsin clearly shows this neutral residue in the P1 pocket, aligned very closely to that seen for lysine in the BPTI:trypsin complex, and proximal to the charged Asp 189 [77]. Apparently, extended binding over the rest of the site compensates for this energetically unfavorable situation. In the P'1 position, the natural cleavage sites use Thr and Ile while Ecotin has Met. In contrast to thrombin, FXa lacks the 60-insertion loop and can accommodate large groups at this position. The BPTI mutants, however, are forced to use a small residue (Ala) because of steric hindrance from the Cys 58- Cys 42 group residue 61 in the enzyme. The inhibitor TFPI-II has a Gly at P'1. The BPTI mutants, TFPI-II, and antistasin all show a preference for aromatic groups at P'2. In the BPTI panning experiments Tyr was selected more than 80% of the time at this position. It can be seen from Table 5 that the Arg to Tyr change at position 17 is one of three significant changes that converts wild type BPTI from a non-Factor Xa inhibitor to a ˜1.6 nM inhibitor. There is a possible hydrogen-bond interaction between Tyr 17 of the inhibitor and Gln 192 of the enzyme, which may explain the strong preference. While models suggest the P'3 residue is directed at solvent and the FXa thrombin cleavage sites have polar residues at this position (Thr, Glu), the BPTI mutant results show a clear preference for a hydrophobic group. It is possible that aromatic groups can pack to Phe 41 of the enzyme. Mutant results show Ile is favored over Phe, His, which in turn is selected over Tyr. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_288.html (1 of 2) [4/5/2004 5:15:07 PM]
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Document RT inhibitor, 41, 56 Nonpe
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Document [Protease targets] serinyl
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