6NJI

Crystal Structure of the PDE4D Catalytic Domain and UCR2 Regulatory Helix with T-49

6NJI の概要

• エントリーDOI: 10.2210/pdb6nji/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: pde4d, camp-specific 3'5'-cyclic phosphodiesterase 4d, ucr2, camp, hydrolase, 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: 2
• 化学式量合計: 86075.20

構造登録者

Fox III, D.,Fairman, J.W.,Gurney, M.E. (登録日: 2019-01-03, 公開日: 2019-05-08, 最終更新日: 2024-03-13)

主引用文献

Gurney, M.E.,Nugent, R.A.,Mo, X.,Sindac, J.A.,Hagen, T.J.,Fox III, D.,O'Donnell, J.M.,Zhang, C.,Xu, Y.,Zhang, H.T.,Groppi, V.E.,Bailie, M.,White, R.E.,Romero, D.L.,Vellekoop, A.S.,Walker, J.R.,Surman, M.D.,Zhu, L.,Campbell, R.F.
Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders.
J.Med.Chem., 62:4884-4901, 2019

PubMed Abstract: Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.

PubMed: 31013090
DOI: 10.1021/acs.jmedchem.9b00193

実験手法

X-RAY DIFFRACTION (2.45 Å)