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PDBsum entry 1rkp
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-Isobutyl-1-Methylxanthine suggest a conformation determinant of inhibitor selectivity.
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Authors
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Q.Huai,
Y.Liu,
S.H.Francis,
J.D.Corbin,
H.Ke.
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Ref.
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J Biol Chem, 2004,
279,
13095-13101.
[DOI no: ]
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PubMed id
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Abstract
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Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes
controlling cellular concentrations of the second messengers cAMP and cGMP.
Crystal structures of the catalytic domains of cGMP-specific PDE5A1 and
cAMP-specific PDE4D2 in complex with the nonselective inhibitor
3-isobutyl-1-methylxanthine have been determined at medium resolution. The
catalytic domain of PDE5A1 has the same topological folding as that of PDE4D2,
but three regions show different tertiary structures, including residues 79-113,
208-224 (H-loop), and 341-364 (M-loop) in PDE4D2 or 535-566, 661-676, and
787-812 in PDE5A1, respectively. Because H- and M-loops are involved in binding
of the selective inhibitors, the different conformations of the loops, thus the
distinct shapes of the active sites, will be a determinant of inhibitor
selectivity in PDEs. IBMX binds to a subpocket that comprises key residues
Ile-336, Phe-340, Gln-369, and Phe-372 of PDE4D2 or Val-782, Phe-786, Gln-817,
and Phe-820 of PDE5A1. This subpocket may be a common site for binding
nonselective inhibitors of PDEs.
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Figure 1.
FIG. 1. Structures of the PDE-IBMX complexes. A, ribbon
diagram of PDE4D2-IBMX. The  -helices are colored as
cyan, and blue color represents 3[10] helices. The first metal
ion is interpreted as zinc, as discussed previously (31, 33),
whereas the second metal ion (Me2) is ambiguous. B, ribbon
diagram of PDE5A1-IBMX. The second metal ion was assigned as
magnesium because 0.2 M MgSO[4] was used in the crystallization
buffer. C, the structural superposition between PDE4D2 and
PDE5A1. The cyan ribbons represent the conserved core structures
between PDE4D2 and PDE5A1. The variable regions are drawn in
gold for PDE4D2 and green for PDE5A1. D, the correspondence of
amino acid sequence to the secondary structures.
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Figure 2.
FIG. 2. IBMX binding. Stereoview of the electron density
for IBMX bound to PDE4D2 (A) and PDE5A1 (B). The 2F[o] - F[c]
maps were calculated from the structures omitted IBMX and
contoured at 1.5  for PDE4D2 and 2.0 for
PDE5A1. C, chemical structure of IBMX. D, IBMX binding to the
active site of PDE4D2. The xanthine group stacks against Phe-372
and forms hydrogen bond with Gln-369 (dotted lines). E, IBMX
binding to the active site of PDE5A1.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
13095-13101)
copyright 2004.
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