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PDBsum entry 2our
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References listed in PDB file
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Key reference
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Title
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Structural insight into substrate specificity of phosphodiesterase 10.
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Authors
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H.Wang,
Y.Liu,
J.Hou,
M.Zheng,
H.Robinson,
H.Ke.
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Ref.
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Proc Natl Acad Sci U S A, 2007,
104,
5782-5787.
[DOI no: ]
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PubMed id
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Abstract
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Phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. It
remains unknown how individual PDE families selectively recognize cAMP and cGMP.
This work reports structural studies on substrate specificity. The crystal
structures of the catalytic domains of the D674A and D564N mutants of PDE10A2 in
complex with cAMP and cGMP reveal that two substrates bind to the active site
with the same syn configuration but different orientations and interactions. The
products AMP and GMP bind PDE10A2 with the anti configuration and interact with
both divalent metals, in contrast to no direct contact of the substrates. The
structures suggest that the syn configurations of cAMP and cGMP are the genuine
substrates for PDE10 and the specificity is achieved through the different
interactions and conformations of the substrates. The PDE10A2 structures also
show that the conformation of the invariant glutamine is locked by two hydrogen
bonds and is unlikely to switch for substrate recognition. Sequence alignment
shows a potential pocket, in which variation of amino acids across PDE families
defines the size and shape of the pocket and thus determines the substrate
specificity.
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Figure 3.
Fig. 3. Binding of products. (A) Interaction of AMP (gold)
with PDE10A2 residues (green). (B) Interaction of GMP with
PDE10A2 residues. (C) Superposition of PDE10A2-AMP over
PDE4D2-AMP (salmon sticks) (27). (D) Superposition of AMP (pink)
over cAMP (gold).
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Figure 4.
Fig. 4. A potential S-pocket. (A) The PDE10A2 residues
(green bonds) are superimposed over the PDE4D2 residues (thinner
salmon sticks). (B) Surface presentation of the S-pocket in
PDE10.
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