3QI3

Crystal structure of PDE9A(Q453E) in complex with inhibitor BAY73-6691

3QI3 の概要

• エントリーDOI: 10.2210/pdb3qi3/pdb
• 関連するPDBエントリー: 3QI4
• 分子名称: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, 1-(2-chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, ZINC ION, ... (5 entities in total)
• 機能のキーワード: mutation, glutamine switch, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 124473.01

構造登録者

Hou, J.,Xu, J.,Liu, M.,Zhao, R.,Lou, H.,Ke, H. (登録日: 2011-01-26, 公開日: 2011-04-27, 最終更新日: 2024-02-21)

主引用文献

Hou, J.,Xu, J.,Liu, M.,Zhao, R.,Luo, H.B.,Ke, H.
Structural asymmetry of phosphodiesterase-9, potential protonation of a glutamic Acid, and role of the invariant glutamine.
Plos One, 6:e18092-e18092, 2011

PubMed Abstract: PDE9 inhibitors show potential for treatment of diseases such as diabetes. To help with discovery of PDE9 inhibitors, we performed mutagenesis, kinetic, crystallographic, and molecular dynamics analyses on the active site residues of Gln453 and its stabilizing partner Glu406. The crystal structures of the PDE9 Q453E mutant (PDE9Q453E) in complex with inhibitors IBMX and (S)-BAY73-6691 showed asymmetric binding of the inhibitors in two subunits of the PDE9Q453E dimer and also the significant positional change of the M-loop at the active site. The kinetic analysis of the Q453E and E406A mutants suggested that the invariant glutamine is critical for binding of substrates and inhibitors, but is unlikely to play a key role in the differentiation between substrates of cGMP and cAMP. The molecular dynamics simulations suggest that residue Glu406 may be protonated and may thus explain the hydrogen bond distance between two side chain oxygens of Glu453 and Glu406 in the crystal structure of the PDE9Q453E mutant. The information from these studies may be useful for design of PDE9 inhibitors.

PubMed: 21483814
DOI: 10.1371/journal.pone.0018092

実験手法

X-RAY DIFFRACTION (2.3 Å)