5WH6

Crystal structure of PDE4D2 in complex with inhibitor (S_Zl-n-91)

5WH6 の概要

• エントリーDOI: 10.2210/pdb5wh6/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, 1-[4-(difluoromethoxy)-3-{[(3S)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one, ZINC ION, ... (5 entities in total)
• 機能のキーワード: phosphodiesterase, inhibitor zl-n-91, pde4d-s91 complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 116551.39

構造登録者

Ke, H.,Wang, H. (登録日: 2017-07-14, 公開日: 2018-07-18, 最終更新日: 2024-03-13)

主引用文献

Feng, X.,Wang, H.,Ye, M.,Xu, X.T.,Xu, Y.,Yang, W.,Zhang, H.T.,Song, G.,Ke, H.
Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors.
Biochemistry, 57:4518-4525, 2018

PubMed Abstract: Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors.

PubMed: 29975048
DOI: 10.1021/acs.biochem.8b00336

実験手法

X-RAY DIFFRACTION (1.6 Å)