Geometry of binding of the Nα‐tosylated piperidides of m‐amidino‐, p‐amidino‐ and p‐guanidino phenylalanine to thrombin and trypsin

FEBS Letters

Bode, Wolfram²  Stürzebecher, Jörg¹  Turk, Dušan² 

[1] Medizinische Akademie Erfurt, D(O)-5010 Erfurt, Germany;Max-Planck-Institut für Biochemie, D(W)-8033 Martinsried, Germany

关键词: Thrombin;    Antithrombotic;    Caogulation;    X-Ray crystal structure;    Inhibitor complex;   

DOI  :  10.1016/0014-5793(91)80033-Y

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The X-ray crystal structures of the complexes formed with bovine trypsin and the Nα-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 Å 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.

【 授权许可】

Unknown