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Title
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Interaction of the peptide CF3-Leu-Ala-NH-C6H4-CF3 (TFLA) with porcine pancreatic elastase. X-ray studies at 1.8 A.
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Authors
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I.Li de la Sierra,
E.Papamichael,
C.Sakarellos,
J.L.Dimicoli,
T.Prangé.
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Ref.
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J Mol Recognit, 1990,
3,
36-44.
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PubMed id
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Abstract
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The peptide trifluoroacetyl-Leu-Ala-(p-trifluoromethylanilide), is a reversible
inhibitor of pancreatic porcine elastase and is characterized by a Km of 2.5 x
10(-8) M. Co-crystals of the 1:1 complex were obtained in an acetate buffer +
dimethylformamide solution at pH 5.7. Diffraction data were recorded on films at
the LURE synchrotron facility. The inhibitor was localized on difference Fourier
maps, and the refinement of the structure was performed by simulated annealing
(XPLOR). The current agreement factor is R = 19% (for 13224 observed structure
factors and 1.8 A effective resolution). The RMS deviations from ideality of
bond distances and angles are 0.02 A and 2 degrees, respectively. The inhibitor
molecule was found in the active site, bent around the side chain of Phe-215 in
a geometry that resembles the previously reported structure of the CF3-Lys-Ala
complex at 2.5 A, in a parallel beta-sheet association with the loop 214-216.
The analysis of the close contacts (less than 3.5 A) indicates that the
trifluoromethylamide bond interacts with the active site and not the Leu-Ala or
Ala-anilide bonds. The two fluorinated groups of the inhibitor exhibit different
specificities: the trifluoroacetyl group (N terminus) is tightly stacked between
the two chain loops 191-195 and 213-215, while the trifluoromethylanilide (C
terminus) shows less specificity and only a single contact.
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