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Titolo:
HIRUNORMS ARE TRUE HIRUDIN MIMETICS - THE CRYSTAL-STRUCTURE OF HUMAN ALPHA-THROMBIN HIRUNORM-V COMPLEX
Autore:
DESIMONE G; LOMBARDI A; GALDIERO S; NASTRI F; DELLAMORTE R; STAIANO N; PEDONE C; BOLOGNESI M; PAVONE V;
Indirizzi:
CTR INTERUNIV RIC PEPTIDI BIOATT,VIA MEZZOCANNONE 4 I-80134 NAPLES ITALY CTR INTERUNIV RIC PEPTIDI BIOATT I-80134 NAPLES ITALY UNIV NAPLES FEDERICO II,CNR,CTR STUDIO BIOCRISTALLOG I-80134 NAPLES ITALY UNIV NAPLES FEDERICO II,DIPARTIMENTO BIOCHIM & BIOTECNOL MED I-80129 NAPLES ITALY UNIV PAVIA,DIPARTIMENTO GENET & MICROBIOL I-27100 PAVIA ITALY UNIV GENOA,ADV BIOTECHNOL CTR I-16132 GENOA ITALY UNIV GENOA,DEPT PHYS I-16132 GENOA ITALY
Titolo Testata:
Protein science
fascicolo: 2, volume: 7, anno: 1998,
pagine: 243 - 253
SICI:
0961-8368(1998)7:2<243:HATHM->2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
PRO-ARG CHLOROMETHYLKETONE; ACTIVE-SITE INHIBITORS; C-TERMINAL REGION; ANTITHROMBIN ACTIVITY; RECOMBINANT HIRUDIN; PEPTIDE INHIBITOR; EXOSITE BINDING; DESIGN; PROTEIN; DOMAIN;
Keywords:
ANTITHROMBOTICS; HIRUDIN-LIKE BINDING MODE; HIRUNORMS; THROMBIN; THROMBIN SYNTHETIC INHIBITORS; X-RAY CRYSTAL STRUCTURE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
73
Recensione:
Indirizzi per estratti:
Citazione:
G. Desimone et al., "HIRUNORMS ARE TRUE HIRUDIN MIMETICS - THE CRYSTAL-STRUCTURE OF HUMAN ALPHA-THROMBIN HIRUNORM-V COMPLEX", Protein science, 7(2), 1998, pp. 243-253

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 a-thrombin and hirunorm V, a 26-residue polypeptide containing non-natural amino acids,determined at 2.1 Angstrom 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 (K-i is in the picomolar range) and thestrong selectivity of hirunorm V. Hirunorm V interacts through the N-terminal tetrapeptide with the thrombin active site in a nonsubstrate mode; at the same time, this inhibitor specifically binds through the C-terminal segment to the fibrinogen recognition exosite, The backboneof the N-terminal tetrapeptide Chg(1) ''-Val(2) ''-2-Nal(3) ''-Thr(4)'' (Chg, cyclohexyl-glycine; 2-Nal, beta-(2-naphthyl)-alanine) forms a short beta-strand parallel to thrombin main-chain residues Ser(214)-Gly(219). The Chg(1) '' side chain fills the S2 subsite, Val(2) '' is located at the entrance of S1, whereas 2-Nal(3) '' side chain occupiesthe aryl-binding site. Such backbone orientation is very close to that observed for the N-terminal residues of hirudin, and it is similar to that of the synthetic retro-binding peptide BMS-183507, but it is opposite to the proposed binding mode of fibrinogen and of small synthetic substrates. Hirunorm V C-terminal segment binds to the fibrinogen recognition exosite, similarly to what observed for hirudin C-terminal tail and related compounds. The linker polypeptide segment connecting hirunorm V Nand C-terminal regions is not observable in the electron density maps. The crystallographic analysis proves the correctness of the design and it provides a compelling proof on the interaction mechanism for this novel class of high potency multisite-directed synthetic thrombin inhibitors.

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Documento generato il 02/12/20 alle ore 14:01:30