1Y2K

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

Summary for 1Y2K

• Entry DOI: 10.2210/pdb1y2k/pdb
• Related: 1Y2B 1Y2C 1Y2D 1Y2E 1Y2H 1Y2J
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: phosphodiesterase, pde, pde4d, pyrazole, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): Q08499
• Total number of polymer chains: 2
• Total formula weight: 82998.96

Authors

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. (deposition date: 2004-11-22, release date: 2005-03-01, Last modification date: 2024-02-14)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.36 Å)