4HTX

Crystal structure of PDE2 catalytic domain in complex with BAY60-7550

4HTX の概要

• エントリーDOI: 10.2210/pdb4htx/pdb
• 関連するPDBエントリー: 4HTZ
• 分子名称: cGMP-dependent 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform PDE2A3: Cell membrane ; Lipid-anchor . Isoform PDE2A2: Mitochondrion matrix . Isoform PDE2A1: Cytoplasm . Isoform 5: Mitochondrion : O00408
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 162128.23

構造登録者

Zhu, J.,Huang, Q. (登録日: 2012-11-02, 公開日: 2013-08-28, 最終更新日: 2023-09-20)

主引用文献

Zhu, J.,Yang, Q.,Dai, D.,Huang, Q.
X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity.
J.Am.Chem.Soc., 135:11708-11711, 2013

PubMed Abstract: To better understand the structural origins of inhibitor selectivity of human phosphodieasterase families (PDEs 1-11), here we report the X-ray crystal structure of PDE2 in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 Å resolution, and the structure of apo PDE2 at 2.0 Å resolution. The crystal structures reveal that the inhibitor binds to the PDE2 active site by using not only the conserved glutamine-switch mechanism for substrate binding, but also a binding-induced, hydrophobic pocket that was not reported previously. In silico affinity profiling by molecular docking indicates that the inhibitor binding to this pocket contributes significantly to the binding affinity and thereby improves the inhibitor selectivity for PDE2. Our results highlight a structure-based design strategy that exploits the potential binding-induced pockets to achieve higher selectivity in the PDE inhibitor development.

PubMed: 23899287
DOI: 10.1021/ja404449g

実験手法

X-RAY DIFFRACTION (1.9 Å)