Biology Reference
In-Depth Information
Structural Insight into the Substrate Specificity
of Phosphodiesterases
Hengming Ke, Huanchen Wang, and Mengchun Ye
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
2 The Active Site of PDEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3 Substrate Specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
4 An Early Proposal for the Substrate Specificity: “Glutamine Switch” . . . . . . . . . . . . . . . . . . . . 127
5 Evidence Against the “Glutamine Switch” Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
6 Binding of the Products Does Not Simulate Binding of the Substrates . . . . . . . . . . . . . . . . . . . 129
7 Equilibrium of
Syn/Anti
Configuration of cAMP and cGMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
8 The Substrate Specificity Is Determined Jointly by Multiple Elements . . . . . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Abstract Cyclic nucleotide phosphodiesterases (PDEs) share a highly conserved
catalytic domain that hydrolyzes cAMP, cGMP, or both nucleotides. However, the
mechanism that allows the PDE catalytic sites to specifically recognize these
nucleotides and distinguish between their subtle differences is still unclear. An
early model, called the “glutamine switch”, proposed that the side chain of an
invariant glutamine adopts two different conformations to allow for formation of
two hydrogen bonds with cAMP and cGMP, thereby differentiating these nucleo-
tides. However, the structure of PDE4D2 in complex with cAMP shows that
Gln369 forms only one hydrogen bond with the substrate. In addition, the structures
of PDE10A in complex with cAMP and cGMP reveal that cAMP and cGMP bind to
the active site in different orientations and have different interactions with PDE10A
residues. These structures suggest that the invariant glutamine does not appear to be
a key residue to differentiate between cAMP and cGMP, although it is important for
substrate binding. The structure-based sequence alignment shows that most of the
active site residues change across PDE families. These residues may not only
contribute differently to the substrate specificity, but also generate slightly different
H. Ke (
*
), H. Wang, and M. Ye
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center,
The University of North Carolina, Chapel Hill, NC 27599-7260, USA
e-mail: hke@med.unc.edu
