2fm5

From Proteopedia

Crystal structure of PDE4D2 in complex with inhibitor L-869299

Overview

Type 4 phosphodiesterase (PDE4) inhibitors are emerging as new treatments, for a number of disorders including asthma and chronic obstructive, pulmonary disease. Here we report the biochemical characterization on the, second generation inhibitor (+)-1 (L-, IC50=0.4 nM) and its enantiomer, (-)-1 (L-, IC50=43 nM) and their cocrystal structures with PDE4D at 2.0 A, resolution. Despite the 107-fold affinity difference, both enantiomers, interact with the same sets of residues in the rigid active site. The, weaker (-)-1 adopts an unfavorable conformation to preserve the pivotal, interactions between the Mg-bound waters and the N-oxide of pyridine., These structures support a model in which inhibitors are anchored by the, invariant glutamine at one end and the metal-pocket residues at another, end. This model provides explanations for most of the observed, structure-activity relationship and the metal ion dependency of the, catechol-ether based inhibitors and should facilitate their further, design.

Disease

Known disease associated with this structure: Stroke, susceptibility to, 1 OMIM:[600129]

About this Structure

2FM5 is a Single protein structure of sequence from Homo sapiens with ZN, MG and M99 as ligands. Active as 3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17 Full crystallographic information is available from OCA.

Reference

Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase., Huai Q, Sun Y, Wang H, Macdonald D, Aspiotis R, Robinson H, Huang Z, Ke H, J Med Chem. 2006 Mar 23;49(6):1867-73. PMID:16539372

Page seeded by OCA on Mon Nov 12 22:07:27 2007