A novel class of synthetic, multisite‐directed thrombin inhibitors, known as hirunorms, has been described recently. These compounds were designed to mimic the binding mode of hirudin, and they have been proven to be very strong and selective thrombin inhibitors. Here we report the crystal structure of the complex formed by human α‐thrombin and hirunorm V, a 26‐residue polypeptide containing non‐natural amino acids, determined at 2.1 Å resolution and refined to an R‐factor of 0.176. The structure reveals that the inhibitor binding mode is distinctive of a true hirudin mimetic, and it highlights the molecular basis of the high inhibitory potency (Ki, is in the picomolar range) and the strong selectivity of hirunorm V.
Hirunorms Are True Hirudin Mimetics. The Crystal Structure of Human α-Thrombin-Hirunorm V Complex / G., DE SIMONE; Lombardi, Angelina; Galdiero, Stefania; Nastri, Flavia; R., DELLA MORTE; N., Staiano; C., Pedone; M., Bolognesi; Pavone, Vincenzo. - In: PROTEIN SCIENCE. - ISSN 0961-8368. - STAMPA. - 7:2(1998), pp. 243-253. [10.1002/pro.5560070203]
Hirunorms Are True Hirudin Mimetics. The Crystal Structure of Human α-Thrombin-Hirunorm V Complex
LOMBARDI, ANGELINA;GALDIERO, STEFANIA;NASTRI, FLAVIA;PAVONE, VINCENZO
1998
Abstract
A novel class of synthetic, multisite‐directed thrombin inhibitors, known as hirunorms, has been described recently. These compounds were designed to mimic the binding mode of hirudin, and they have been proven to be very strong and selective thrombin inhibitors. Here we report the crystal structure of the complex formed by human α‐thrombin and hirunorm V, a 26‐residue polypeptide containing non‐natural amino acids, determined at 2.1 Å resolution and refined to an R‐factor of 0.176. The structure reveals that the inhibitor binding mode is distinctive of a true hirudin mimetic, and it highlights the molecular basis of the high inhibitory potency (Ki, is in the picomolar range) and the strong selectivity of hirunorm V.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.