4NW7

PDE4 catalytic domain

Summary for 4NW7

• Entry DOI: 10.2210/pdb4nw7/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4B, ZINC ION, MAGNESIUM ION, ... (7 entities in total)
• Functional Keywords: phosphodiesterase, pde4, catalytic, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 43679.10

Authors

Fox III, D.,Edwards, T.E. (deposition date: 2013-12-05, release date: 2014-10-15, Last modification date: 2024-02-28)

Primary citation

Hagen, T.J.,Mo, X.,Burgin, A.B.,Fox, D.,Zhang, Z.,Gurney, M.E.
Discovery of triazines as selective PDE4B versus PDE4D inhibitors.
Bioorg.Med.Chem.Lett., 24:4031-4034, 2014

PubMed Abstract: In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.

PubMed: 24998378
DOI: 10.1016/j.bmcl.2014.06.002

Experimental method

X-RAY DIFFRACTION (2.15 Å)