A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases.
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.
Zhang
Kam Y J
KY
Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA.
Card
Graeme L
GL
Suzuki
Yoshihisa
Y
Artis
D Richard
DR
Fong
Daniel
D
Gillette
Sam
S
Hsieh
Davin
D
Neiman
Joshua
J
West
Brian L
BL
Zhang
Chao
C
Milburn
Michael V
MV
Kim
Sung-Hou
SH
Schlessinger
Joseph
J
Bollag
Gideon
G
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
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