1Y2J

Catalytic Domain Of Human Phosphodiesterase 4B In Complex With 3,5-dimethyl-1-(3-nitro-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

1Y2J の概要

• エントリーDOI: 10.2210/pdb1y2j/pdb
• 関連するPDBエントリー: 1Y2B 1Y2C 1Y2D 1Y2E 1Y2H 1Y2K
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4B, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: phosphodiesterase, pde, pde4b, pyrazole, hydrolase
• 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: 92220.67

構造登録者

Card, G.L.,Blasdel, L.,England, B.P.,Zhang, C.,Suzuki, Y.,Gillette, S.,Fong, D.,Ibrahim, P.N.,Artis, D.R.,Bollag, G.,Milburn, M.V.,Kim, S.-H.,Schlessinger, J.,Zhang, K.Y.J. (登録日: 2004-11-22, 公開日: 2005-03-01, 最終更新日: 2011-07-13)

主引用文献

Card, G.L.,Blasdel, L.,England, B.P.,Zhang, C.,Suzuki, Y.,Gillette, S.,Fong, D.,Ibrahim, P.N.,Artis, D.R.,Bollag, G.,Milburn, M.V.,Kim, S.-H.,Schlessinger, J.,Zhang, K.Y.J.
A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design
Nat.Biotechnol., 23:201-207, 2005

PubMed Abstract: Cyclic nucleotide phosphodiesterases (PDEs) comprise a large family of enzymes that regulate a variety of cellular processes. We describe a family of potent PDE4 inhibitors discovered using an efficient method for scaffold-based drug design. This method involves an iterative approach starting with low-affinity screening of compounds followed by high-throughput cocrystallography to reveal the molecular basis underlying the activity of the newly identified compounds. Through detailed structural analysis of the interaction of the initially discovered pyrazole carboxylic ester scaffold with PDE4D using X-ray crystallography, we identified three sites of chemical substitution and designed small selective libraries of scaffold derivatives with modifications at these sites. A 4,000-fold increase in the potency of this PDE4 inhibitor was achieved after only two rounds of chemical synthesis and the structural analysis of seven pyrazole derivatives bound to PDE4B or PDE4D, revealing the robustness of this approach for identifying new inhibitors that can be further developed into drug candidates.

PubMed: 15685167
DOI: 10.1038/nbt1059

実験手法

X-RAY DIFFRACTION (2.55 Å)