3K3E

Crystal structure of the PDE9A catalytic domain in complex with (R)-BAY73-6691

3K3E の概要

• エントリーDOI: 10.2210/pdb3k3e/pdb
• 関連するPDBエントリー: 3K3H
• 分子名称: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: pde9, catalytic domain, cgmp, hydrolase, manganese, metal-binding, phosphoprotein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform PDE9A1: Cell projection, ruffle membrane. Isoform PDE9A2: Cell projection, ruffle membrane. Isoform PDE9A3: Cytoplasm. Isoform PDE9A17: Cytoplasm: O76083
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 77986.03

構造登録者

Wang, H.,Luo, X.,Ye, M.,Hou, J.,Robinson, H.,Ke, H. (登録日: 2009-10-02, 公開日: 2010-02-16, 最終更新日: 2024-11-06)

主引用文献

Wang, H.,Luo, X.,Ye, M.,Hou, J.,Robinson, H.,Ke, H.
Insight into Binding of Phosphodiesterase-9A Selective Inhibitors by Crystal Structures and Mutagenesis
J.Med.Chem., 53:1726-1731, 2010

PubMed Abstract: PDE9 inhibitors have been studied as therapeutics for treatment of cardiovascular diseases, diabetes, and neurodegenerative disorders. To illustrate the inhibitor selectivity, the crystal structures of the PDE9A catalytic domain in complex with the enantiomers of PDE9 inhibitor 1-(2-chlorophenyl)-6-(3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine-4(5H)-one ((R)-BAY73-6691 or (S)-BAY73-6691, 1r or 1s) were determined and mutagenesis was performed. The structures showed that the fluoromethyl groups of 1r and 1s had different orientations while the other parts of the inhibitors commonly interacted with PDE9A. These differences may explain the slightly different affinity of 1r (IC(50) = 22 nM) and 1s (IC(50) = 88 nM). The mutagenesis experiments revealed that contribution of the binding residues to the inhibitor sensitivity varies dramatically, from few-fold to 3 orders of magnitude. On the basis of the crystal structures, a hypothesized compound that simulates the recently published PDE9 inhibitors was modeled to provide insight into the inhibitor selectivity.

PubMed: 20121115
DOI: 10.1021/jm901519f

実験手法

X-RAY DIFFRACTION (2.7 Å)