6BOJ

Crystal Structure of the PDE4D Catalytic Domain and UCR2 Regulatory Helix with BPN5004

6BOJ の概要

• エントリーDOI: 10.2210/pdb6boj/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: pde4d, camp-specific 3'5'-cyclic phosphodiesterase 4d, ucr2, camp, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 172703.46

構造登録者

Fox III, D.,Fairman, J.W.,Gurney, M.E. (登録日: 2017-11-20, 公開日: 2018-08-22, 最終更新日: 2024-03-13)

主引用文献

Zhang, C.,Xu, Y.,Chowdhary, A.,Fox 3rd., D.,Gurney, M.E.,Zhang, H.T.,Auerbach, B.D.,Salvi, R.J.,Yang, M.,Li, G.,O'Donnell, J.M.
Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice.
Neuropsychopharmacology, 43:2299-2309, 2018

PubMed Abstract: Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.

PubMed: 30131563
DOI: 10.1038/s41386-018-0178-6

実験手法

X-RAY DIFFRACTION (1.7 Å)