title: Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity.
abstract: Phosphodiesterases (PDEs) are enzymes that modulate cyclic nucleotide signaling and as such are clinical targets for a range of disorders including congestive heart failure, erectile dysfunction, and inflammation. The PDE3 family comprises two highly homologous subtypes expressed in different tissues, and inhibitors of this family have been shown to increase lipolysis in adipocytes. A specific PDE3B (the lipocyte-localized subtype) inhibitor would be a very useful tool to evaluate the effects of PDE3 inhibition on lipolysis and metabolic rate and might become a novel tool for treatment of obesity. We report here the three-dimensional structures of the catalytic domain of human PDE3B in complex with a generic PDE inhibitor and a novel PDE3 selective inhibitor. These structures explain the dual cAMP/cGMP binding capabilities of PDE3, provide the molecular basis for inhibitor specificity, and can supply a valid platform for the design of improved compounds.
authors.affiliation: Departments of Medicinal Chemistry, Merck & Co., Rahway, New Jersey 07065, USA. giovanna_scapin@merck.com
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.forename: Christine
authors.initials: C
authors.lastname: Chung
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Varnerin
authors.forename: Scott D
authors.initials: SD
authors.lastname: Edmondson
authors.forename: Anthony
authors.initials: A
authors.lastname: Mastracchio
authors.forename: Emma R
authors.initials: ER
authors.lastname: Parmee
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Singh
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Becker
authors.forename: Lex H T
authors.initials: LH
authors.lastname: Van der Ploeg
authors.forename: Michael R
authors.initials: MR
authors.lastname: Tota
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000737:chemistry / Q000378:metabolism; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000737:chemistry; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D019281:Dimerization; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517291:PDE3B protein, human; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine