Back to Search
Start Over
Structural basis for the design of selective phosphodiesterase 4B inhibitors.
Structural basis for the design of selective phosphodiesterase 4B inhibitors.
- Source :
-
Cellular signalling [Cell Signal] 2014 Mar; Vol. 26 (3), pp. 657-63. Date of Electronic Publication: 2013 Dec 19. - Publication Year :
- 2014
-
Abstract
- Phosphodiesterase-4B (PDE4B) regulates the pro-inflammatory Toll Receptor -Tumor Necrosis Factor α (TNFα) pathway in monocytes, macrophages and microglial cells. As such, it is an important, although under-exploited molecular target for anti-inflammatory drugs. This is due in part to the difficulty of developing selective PDE4B inhibitors as the amino acid sequence of the PDE4 active site is identical in all PDE4 subtypes (PDE4A-D). We show that highly selective PDE4B inhibitors can be designed by exploiting sequence differences outside the active site. Specifically, PDE4B selectivity can be achieved by capture of a C-terminal regulatory helix, now termed CR3 (Control Region 3), across the active site in a conformation that closes access by cAMP. PDE4B selectivity is driven by a single amino acid polymorphism in CR3 (Leu674 in PDE4B1 versus Gln594 in PDE4D). The reciprocal mutations in PDE4B and PDE4D cause a 70-80 fold shift in selectivity. Our structural studies show that CR3 is flexible and can adopt multiple orientations and multiple registries in the closed conformation. The new co-crystal structure with bound ligand provides a guide map for the design of PDE4B selective anti-inflammatory drugs.<br /> (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Sequence genetics
Anti-Inflammatory Agents pharmacology
Catalytic Domain drug effects
Crystallography, X-Ray
Cyclic Nucleotide Phosphodiesterases, Type 4 drug effects
Drug Design
Macrophages metabolism
Microglia metabolism
Models, Molecular
Monocytes metabolism
Phosphodiesterase 4 Inhibitors pharmacology
Polymorphism, Genetic
Tumor Necrosis Factor-alpha biosynthesis
Anti-Inflammatory Agents chemical synthesis
Anti-Inflammatory Agents chemistry
Catalytic Domain genetics
Phosphodiesterase 4 Inhibitors chemical synthesis
Phosphodiesterase 4 Inhibitors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1873-3913
- Volume :
- 26
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cellular signalling
- Publication Type :
- Academic Journal
- Accession number :
- 24361374
- Full Text :
- https://doi.org/10.1016/j.cellsig.2013.12.003