title: A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases.
abstract: Phosphodiesterases (PDEs) comprise a family of enzymes that modulate the immune response, inflammation, and memory, among many other functions. There are three types of PDEs: cAMP-specific, cGMP-specific, and dual-specific. Here we describe the mechanism of nucleotide selectivity on the basis of high-resolution co-crystal structures of the cAMP-specific PDE4B and PDE4D with AMP, the cGMP-specific PDE5A with GMP, and the apo-structure of the dual-specific PDE1B. These structures show that an invariant glutamine functions as the key specificity determinant by a "glutamine switch" mechanism for recognizing the purine moiety in cAMP or cGMP. The surrounding residues anchor the glutamine residue in different orientations for cAMP and for cGMP. The PDE1B structure shows that in dual-specific PDEs a key histidine residue may enable the invariant glutamine to toggle between cAMP and cGMP. The structural understanding of nucleotide binding enables the design of new PDE inhibitors that may treat diseases in which cyclic nucleotides play a critical role.
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA.
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.forename: Graeme L
authors.initials: GL
authors.lastname: Card
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Suzuki
authors.forename: D Richard
authors.initials: DR
authors.lastname: Artis
authors.forename: Daniel
authors.initials: D
authors.lastname: Fong
authors.forename: Sam
authors.initials: S
authors.lastname: Gillette
authors.forename: Davin
authors.initials: D
authors.lastname: Hsieh
authors.forename: Joshua
authors.initials: J
authors.lastname: Neiman
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: Sung-Hou
authors.initials: SH
authors.lastname: Kim
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000737:chemistry* / Q000378:metabolism; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D005973:Glutamine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D005973:Glutamine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C517376:PDE4D protein, human; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP