3G45

Crystal structure of human phosphodiesterase 4b with regulatory domain and d155988

Summary for 3G45

• Entry DOI: 10.2210/pdb3g45/pdb
• Related: 3G4G 3G4I 3G4K 3G4L 3G58 3GPZ
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4B, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase, alternative splicing, camp, hydrolase, phosphoprotein, polymorphism
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 97747.55

Authors

Staker, B.L. (deposition date: 2009-02-03, release date: 2010-01-19, Last modification date: 2024-02-21)

Primary citation

Burgin, A.B.,Magnusson, O.T.,Singh, J.,Witte, P.,Staker, B.L.,Bjornsson, J.M.,Thorsteinsdottir, M.,Hrafnsdottir, S.,Hagen, T.,Kiselyov, A.S.,Stewart, L.J.,Gurney, M.E.
Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
Nat.Biotechnol., 28:63-70, 2010

PubMed Abstract: Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.

PubMed: 20037581
DOI: 10.1038/nbt.1598

Experimental method

X-RAY DIFFRACTION (2.63 Å)