1o2g

From Proteopedia

Revision as of 14:31, 15 February 2008

Elaborate Manifold of Short Hydrogen Bond Arrays Mediating Binding of Active Site-Directed Serine Protease Inhibitors

Overview

An extensive structural manifold of short hydrogen bond-mediated, active, site-directed, serine protease inhibition motifs is revealed in a set of, over 300 crystal structures involving a large suite of small molecule, inhibitors (2-(2-phenol)-indoles and 2-(2-phenol)-benzimidazoles), determined over a wide range of pH (3.5-11.4). The active site, hydrogen-bonding mode was found to vary markedly with pH, with the steric, and electronic properties of the inhibitor, and with the type of protease, (trypsin, thrombin or urokinase type plasminogen activator (uPA)). The pH, dependence of the active site hydrogen-bonding motif is often intricate, constituting a distinct fingerprint of each complex. Isosteric, replacements or minor substitutions within the inhibitor that modulate the, pK(a) of the phenol hydroxyl involved in short hydrogen bonding, or that, affect steric interactions distal to the active site, can significantly, shift the pH-dependent structural profile characteristic of the parent, scaffold, or produce active site-binding motifs unique to the bound, analog.Ionization equilibria at the active site associated with inhibitor, binding are probed in a series of the protease-inhibitor complexes through, analysis of the pH dependence of the structure and environment of the, active site-binding groups involved in short hydrogen bond arrays., Structures determined at high pH (>11), suggest that the pK(a) of His57 is, dramatically elevated, to a value as high as approximately 11 in certain, complexes. K(i) values involving uPA and trypsin determined as a function, of pH for a set of inhibitors show pronounced parabolic pH dependence, the, pH for optimal inhibition governed by the pK(a) of the inhibitor phenol, involved in short hydrogen bonds. Comparison of structures of trypsin, thrombin and uPA, each bound by the same inhibitor, highlights important, structural variations in the S1 and active sites accessible for, engineering notable selectivity into remarkably small molecules with low, nanomolar K(i) values.

Disease

Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

1O2G is a Protein complex structure of sequences from Homo sapiens with and as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

Elaborate manifold of short hydrogen bond arrays mediating binding of active site-directed serine protease inhibitors., Katz BA, Elrod K, Verner E, Mackman RL, Luong C, Shrader WD, Sendzik M, Spencer JR, Sprengeler PA, Kolesnikov A, Tai VW, Hui HC, Breitenbucher JG, Allen D, Janc JW, J Mol Biol. 2003 May 23;329(1):93-120. PMID:12742021

Page seeded by OCA on Fri Feb 15 16:31:58 2008