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PDBsum entry 4x0f
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Hydrolase/hydrolase inhibitor
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PDB id
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4x0f
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References listed in PDB file
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Key reference
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Title
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Engineered stabilization and structural analysis of the autoinhibited conformation of pde4.
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Authors
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P.Cedervall,
A.Aulabaugh,
K.F.Geoghegan,
T.J.Mclellan,
J.Pandit.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
E1414.
[DOI no: ]
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PubMed id
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Abstract
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Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular
signaling and an important drug target. The four members of this enzyme family
(PDE4A to -D) are functional dimers in which each subunit contains two upstream
conserved regions (UCR), UCR1 and -2, which precede the C-terminal catalytic
domain. Alternative promoters, transcriptional start sites, and mRNA splicing
lead to the existence of over 25 variants of PDE4, broadly classified as long,
short, and supershort forms. We report the X-ray crystal structure of long form
PDE4B containing UCR1, UCR2, and the catalytic domain, crystallized as a dimer
in which a disulfide bond cross-links cysteines engineered into UCR2 and the
catalytic domain. Biochemical and mass spectrometric analyses showed that the
UCR2-catalytic domain interaction occurs in trans, and established that this
interaction regulates the catalytic activity of PDE4. By elucidating the key
structural determinants of dimerization, we show that only long forms of PDE4
can be regulated by this mechanism. The results also provide a structural basis
for the long-standing observation of high- and low-affinity binding sites for
the prototypic inhibitor rolipram.
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