3IAD

Crystal structure of human phosphodiesterase 4D with bound allosteric modulator

3IAD の概要

• エントリーDOI: 10.2210/pdb3iad/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, 1-{4-[(2-fluoro-6-methoxy-3'-nitrobiphenyl-3-yl)methyl]phenyl}urea, ZINC ION, ... (6 entities in total)
• 機能のキーワード: pde4d, allosteric modulatory, inhibitor, ucr2, alternative splicing, camp, cytoplasm, cytoskeleton, hydrolase, membrane, metal-binding, phosphoprotein
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Apical cell membrane : Q08499
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 177286.11

構造登録者

Staker, B.L.,Burgin Jr., A.B. (登録日: 2009-07-13, 公開日: 2010-01-05, 最終更新日: 2024-02-21)

主引用文献

Burgin, A.B.,Magnusson, O.T.,Singh, J.,Witte, P.,Staker, B.L.,Bjornsson, J.M.,Thorsteinsdottir, M.,Hrafnsdottir, S.,Hagen, T.,Kiselyov, A.S.,Stewart, L.J.,Gurney, M.E.
Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
Nat.Biotechnol., 28:63-70, 2010

PubMed Abstract: Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.

PubMed: 20037581
DOI: 10.1038/nbt.1598

実験手法

X-RAY DIFFRACTION (2.65 Å)