1XLX

Catalytic Domain Of Human Phosphodiesterase 4B In Complex With Cilomilast

Summary for 1XLX

• Entry DOI: 10.2210/pdb1xlx/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4B, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde4b, cilomilast, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 92328.93

Authors

Card, G.L.,England, B.P.,Suzuki, Y.,Fong, D.,Powell, B.,Lee, B.,Luu, C.,Tabrizizad, M.,Gillette, S.,Ibrahim, P.N.,Artis, D.R.,Bollag, G.,Milburn, M.V.,Kim, S.-H.,Schlessinger, J.,Zhang, K.Y.J. (deposition date: 2004-09-30, release date: 2004-12-14, Last modification date: 2024-10-30)

Primary citation

Card, G.L.,England, B.P.,Suzuki, Y.,Fong, D.,Powell, B.,Lee, B.,Luu, C.,Tabrizizad, M.,Gillette, S.,Ibrahim, P.N.,Artis, D.R.,Bollag, G.,Milburn, M.V.,Kim, S.-H.,Schlessinger, J.,Zhang, K.Y.J.
Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases.
Structure, 12:2233-2247, 2004

PubMed Abstract: Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.

PubMed: 15576036
DOI: 10.1016/j.str.2004.10.004

Experimental method

X-RAY DIFFRACTION (2.19 Å)