7B9H

Crystal structure of the PDE4D catalytic domain in complex with GEBR-42a

7B9H の概要

• エントリーDOI: 10.2210/pdb7b9h/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: phosphodiesterase 4d, inhibitor, complex, gebr, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82094.00

構造登録者

Torretta, A.,Abbate, S.,Parisini, E. (登録日: 2020-12-14, 公開日: 2021-06-30, 最終更新日: 2025-10-01)

主引用文献

Brullo, C.,Rapetti, F.,Abbate, S.,Prosdocimi, T.,Torretta, A.,Semrau, M.,Massa, M.,Alfei, S.,Storici, P.,Parisini, E.,Bruno, O.
Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors.
Eur.J.Med.Chem., 223:113638-113638, 2021

PubMed Abstract: Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme. Here, based on those findings, we describe further chemical modifications of the protruding subset of GEBR library inhibitors and their effects on ligand conformation and potency. In particular, we demonstrate that the insertion of a methyl group in the flexible linker region connecting the catechol portion and the basic end of the molecules enhances the ability of the ligand to interact with both the catalytic and the regulatory domains of the enzyme.

PubMed: 34171658
DOI: 10.1016/j.ejmech.2021.113638

実験手法

X-RAY DIFFRACTION (1.5 Å)