Biology Reference
In-Depth Information
PDE4D2-AMP complex changes its conformation in the unliganded state to form
two hydrogen bonds with N
6
and N7 of 5
0
-AMP. In comparison, Asn321 in the
PDE4D2-cAMP complex when compared with the unliganded state retains its
conformation and does not form hydrogen bonds with cAMP. Finally, two hydrogen
bonds are formed between N1 and N
6
of 5
0
-AMP and N
e
2 and O
e
1 of Gln369 in the
PDE4D2-AMP complex. In contrast, Gln369 in the PDE4D2-cAMP structure forms
only one hydrogen bond with N1 of cAMP, and the distance of 3.7
˚
between O
e
1
of Gln369 and N
6
of cAMP indicates their weak van der Waals' interaction (Fig.
4a
).
The observation of only one hydrogen bond between cAMP and the invariant
glutamine in the PDE4D2-cAMP structure provides direct evidence against the
mechanism of “glutamine switch”, in which two hydrogen bonds were assumed
(Zhang et al.
2004
).
Further support for the argument that the 5
0
-nucleotide products are not good
models for substrates comes from the structures of PDE10A (Wang et al.
2007a
).
These structures showed that both substrates cAMP and cGMP bound to PDE10A
with the
syn
configuration, but the products (5
0
-AMP and 5
0
-GMP) are in the
anti
configuration (Fig.
5
). These different conformations lead to different interactions
in terms of hydrogen bonding and van der Waal's contacts. In summary, the
different conformations between the substrates and products in the PDE10 struc-
tures and the different hydrogen bonding pattern in PDE4 strongly support the
conclusion that the products of cN hydrolysis are not reasonable models for
describing the details of substrate binding.
Fig. 5 Comparison of binding of substrates and products in the PDE10 structures. (a) cAMP
(
golden
bonds) has an orientation different from cGMP (
pink
bonds). The colors
blue
and
green
represent residues from the cAMP and cGMP structures, respectively. (b) Superposition of
PDE10-cAMP (
blue and golden
bonds) over PDE10-AMP (
green
and
pink
bonds).
Dotted lines
represent hydrogen bonds or coordination with the metal ions. (c) superposition of PDE10-cGMP
(blue and golden bonds) over PDE10-GMP (
green
and
pink
bonds)
