6F8W

Crystal structure of the PDE4D catalytic domain in complex with GEBR-18a

6F8W の概要

• エントリーDOI: 10.2210/pdb6f8w/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: pde4, catalytic domain, inhibitor, gebr, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Apical cell membrane : Q08499
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80301.20

構造登録者

Prosdocimi, T.,Donini, S.,Parisini, E. (登録日: 2017-12-13, 公開日: 2018-05-16, 最終更新日: 2024-01-17)

主引用文献

Prosdocimi, T.,Mollica, L.,Donini, S.,Semrau, M.S.,Lucarelli, A.P.,Aiolfi, E.,Cavalli, A.,Storici, P.,Alfei, S.,Brullo, C.,Bruno, O.,Parisini, E.
Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds.
Biochemistry, 57:2876-2888, 2018

PubMed Abstract: Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure-activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms.

PubMed: 29652483
DOI: 10.1021/acs.biochem.8b00288

実験手法

X-RAY DIFFRACTION (1.601 Å)