Geometry of binding of the benzamidine‐ and arginine‐based inhibitors Nα‐(2‐naphthyl‐sulphonyl‐glycyl)‐dl‐p‐amidinophenylalanyl‐piperidine (NAPAP) and (2R,4R)‐4‐methyl‐1‐[Nα‐(3‐methyl‐1,2,3,4‐tetrahydro‐8‐quinolinesulphonyl)‐l‐arginyl]‐2‐piperidine carboxylic acid (MQPA) to human α‐thrombin

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Abstract
The X‐ray crystal structure of the trypsin complex formed with Nα‐(2‐naphthyl‐sulphonyl‐glycyl)‐dl‐p‐amidinophenylalanyl‐piperidine (NAPAP) was determined with X‐ray data to 0.18‐nm resolution and crystallographically refined. NAPAP binds into the active site of trypsin in a quite compact form: the p‐amidinophenylalanine moiety of the d‐stereoisomer binds into the specificity pocket; the glycyl group is hydrogen bonded with Gly216; the naphthyl group stands perpendicular to the indole moiety of Trp215; the piperidine ring is tightly packed between this naphthyl moiety and His57; in consequence the carboxy‐terminal amido bond of NAPAP is located in such a way that it is not susceptible to the active‐site Ser195. NAPAP and (2R,4R)‐4‐methyl‐1‐[Nα‐(3‐methyl‐1,2,3,4‐tetrahydro‐8‐quinolinesulphonyl)‐l‐arginyl]‐2‐piperidine carboxylic acid (MQPA) [Matzusaki, T., Sasaki, C., Okumura, C. & Umeyama (1989) J. Biochem. (Tokyo) 105, 949–952] were transferred in their trypsin‐binding conformations to human α‐thrombin [Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S. R. & Hofsteenge, J. (1989) EMBO J. 8, 3467–3475] and energy minimized. Both synthetic inhibitors fit perfectly into the much more restricted active site of thrombin. The accommodation of the S‐aryl moieties in the ‘aryl‐binding site’ and of the piperidine rings in the S2 subsite of thrombin are particularly favourable. The preference of thrombin for distinctly substituted piperidine derivatives and its generally higher (compared with trypsin) affinity for benzamidine and arginine‐based inhibitors can be accounted for by these thrombin inhibitor models.

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