Potent Bivalent Inhibition of Human Tryptase-? by a Synthetic Inhibitor
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| 008 | 161128e20031225xx s 000 0 eng | ||
| 024 | 7 | 0 | |a 10.1515/BC.2003.178 |2 doi |
| 035 | |a (NATIONALLICENCE)gruyter-10.1515/BC.2003.178 | ||
| 245 | 0 | 0 | |a Potent Bivalent Inhibition of Human Tryptase-? by a Synthetic Inhibitor |h [Elektronische Daten] |c [T. Selwood, K.C. Elrod, N. M. Schechter] |
| 520 | 3 | |a Human tryptase-? (HT?) is a unique serine protease exhibiting a frame-like tetramer structure with four active sites directed toward a central pore. Potent inhibition of HT? has been attained using CRA-2059. This compound has two phenylguanidinium head groups connected via a linker capable of spanning between two active sites. The properties of the CRA-2059:HT? interaction were defined in this study. Tightbinding reversible inhibition was observed with an inhibition constant (Ki) of 620 pM, an association rate constant of 7×07 M -1s-1 and a relatively slow dissociation rate constant of 0.04 s-1. Bivalent inhibition was demonstrated by displacement of paminobenzamidine from the primary specificity pocket with a stoichiometry, [CRA-2059]0/[HT?]0, of 0.5. The potency of the bivalent interaction was illustrated by CRA-2059 inhibition of HT?, 24% or 53% inhibited by preincubation with an irreversible inhibitor. Two interactions were observed consistent with mono and bivalent binding; the Ki value for bivalent inhibition was at least 104-fold lower than that for monovalent inhibition. Comparison of the affinities of CRA-2059 and phenylguanidine for HT? finds an approximate doubling of the free energy change upon bivalent binding. This doubling suggests that the linker portion minimally hinders the binding of CRA-2059 to HT?. The potency of CRA-2059 is thus attributable to effective bivalent binding. | |
| 540 | |a Copyright © 2003 by Walter de Gruyter GmbH & Co. KG | ||
| 690 | 7 | |a Biochemistry |2 nationallicence | |
| 690 | 7 | |a Molecular biology |2 nationallicence | |
| 690 | 7 | |a Cellular biology |2 nationallicence | |
| 700 | 1 | |a Selwood |D T. |4 aut | |
| 700 | 1 | |a Elrod |D K.C. |4 aut | |
| 700 | 1 | |a Schechter |D N. M. |4 aut | |
| 773 | 0 | |t Biological Chemistry |d Walter de Gruyter |g 384/12(2003-12-25), 1605-1611 |x 1431-6730 |q 384:12<1605 |1 2003 |2 384 |o bchm | |
| 856 | 4 | 0 | |u https://doi.org/10.1515/BC.2003.178 |q text/html |z Onlinezugriff via DOI |
| 908 | |D 1 |a research article |2 jats | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1515/BC.2003.178 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Selwood |D T. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Elrod |D K.C. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Schechter |D N. M. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Biological Chemistry |d Walter de Gruyter |g 384/12(2003-12-25), 1605-1611 |x 1431-6730 |q 384:12<1605 |1 2003 |2 384 |o bchm | ||
| 900 | 7 | |b CC0 |u http://creativecommons.org/publicdomain/zero/1.0 |2 nationallicence | |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-gruyter | ||