1tbf
Catalytic Domain Of Human Phosphodiesterase 5A in Complex with Sildenafil
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OverviewOverview
Phosphodiesterases (PDEs) comprise a family of enzymes that modulate the, immune response, inflammation, and memory, among many other functions., There are three types of PDEs: cAMP-specific, cGMP-specific, and, dual-specific. Here we describe the mechanism of nucleotide selectivity on, the basis of high-resolution co-crystal structures of the cAMP-specific, PDE4B and PDE4D with AMP, the cGMP-specific PDE5A with GMP, and the, apo-structure of the dual-specific PDE1B. These structures show that an, invariant glutamine functions as the key specificity determinant by a, "glutamine switch" mechanism for recognizing the purine moiety in cAMP or, cGMP. The surrounding residues anchor the glutamine residue in different, orientations for cAMP and for cGMP. The PDE1B structure shows that in, dual-specific PDEs a key histidine residue may enable the invariant, glutamine to toggle between cAMP and cGMP. The structural understanding of, nucleotide binding enables the design of new PDE inhibitors that may treat, diseases in which cyclic nucleotides play a critical role.
About this StructureAbout this Structure
1TBF is a Single protein structure of sequence from Homo sapiens with ZN, MG, VIA and GOL as ligands. Active as 3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17 Full crystallographic information is available from OCA.
ReferenceReference
A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases., Zhang KY, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, Hsieh D, Neiman J, West BL, Zhang C, Milburn MV, Kim SH, Schlessinger J, Bollag G, Mol Cell. 2004 Jul 23;15(2):279-86. PMID:15260978
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