Biology Reference
In-Depth Information
Fig. 6 The putative substrate-specificity pocket (S-pocket). (a) The PDE10A2 residues (
green
bonds) are superimposed over the PDE4D2 residues (thinner salmon sticks). (b) Surface presenta-
tion of the S-pocket in PDE10
one substrate would not effectively bind to the pocket, due to the poor apparent
affinity constants (K
M
) in the millimolar range (Table
2
).
In summary, the structural and biochemical studies support the interpretation
that the substrate specificity of PDEs is jointly determined by multiple elements in
the PDE catalytic S-pocket and that no individual residues play a dominant role.
Moreover, the structural data suggests that amino acids in the S-pocket may
contribute importantly and distinctly to the substrate specificity in different PDE
families, yet their quantitative roles in this process need further study.
References
Antoni F (2000) Molecular diversity of cyclic AMP signaling. Front Neuroendocrinol 21:103-132
Beavo JA, Hardman JG, Sutherland EW (1970) Hydrolysis of cyclic guanosine and adenosine 3',
5'-monophosphates by rat and bovine tissues. J Biol Chem 245:5649-5655
Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to
clinical use. Pharmacol Rev 58:488-520
Bolger GB, Erdogan S, Jones RE, Loughney K, Scotland G, Hoffmann R, Wilkinson I, Farrell C,
Houslay MD (1997) Characterization of five different proteins produced by alternatively
spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene. Biochem J
328:539-548
Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M,
Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME (2010) Design of phosphodi-
esterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat
Biotechnol 28:63-70
Butcher RW, Sutherland EW (1962) Adenosine 3', 5'-phosphate in biological materials. I.
purification and properties of cyclic 3'5'-nucleotide phosphodiesterase and use of this enzyme
to characterize adenosine 3', 5'-phosphate in human urine. J Biol Chem 237:1244-1250
