Geometry of binding of the N alpha-tosylated piperidides of m-amidino-, p-amidino- and p-guanidino phenylalanine to thrombin and trypsin. X-ray crystal structures of their trypsin complexes and modeling of their thrombin complexes.

Abstract:

:The X-ray crystal structures of the complexes formed with bovine trypsin and the N alpha-tosylated piperidides of m-amidino-, p-amidino- and p-guanidino-D,L-phenylalanine (3-TAPAP, 4-TAPAP and 4-TGPAP) were determined with data to 1.8 A resolution. The L-stereoisomer of 3-TAPAP binds as a compact entity into the active site of trypsin, with the amidino and the carbonyl groups of the central amidinophenylalanyl residue hydrogen-bonded to Gly216 of trypsin. According to modeling and energy minimization, 3-TAPAP fits perfectly in this conformation to the more restrictive thrombin active site also (Bajusz et al. (1978) Int. J. Pept. Prot. Res. 12, 217-221); the piperidine moiety extends into the cage-like S2 subsite of thrombin, but leaves room for additional substituents which might help to improve binding and pharmacological properties. In contrast, 4-TAPAP and 4-TGPAP bind only weakly and in an extended conformation to trypsin; their considerably enhanced affinities for thrombin would suggest a more compact binding to thrombin.

journal_name

FEBS Lett

journal_title

FEBS letters

authors

Turk D,Stürzebecher J,Bode W

doi

10.1016/0014-5793(91)80033-y

subject

Has Abstract

pub_date

1991-08-05 00:00:00

pages

133-8

issue

1-2

eissn

0014-5793

issn

1873-3468

pii

0014-5793(91)80033-Y

journal_volume

287

pub_type

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