2k31

Solution Structure of cGMP-binding GAF domain of Phosphodiesterase 5

spinqualitylabelsall models 2k31, 20 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2k31 is a 1 chain structure with sequence from Mus musculus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 35G Gene: Pde5a (Mus musculus) Activity: 3',5'-cyclic-GMP phosphodiesterase, with EC number 3.1.4.35 Resources: FirstGlance, OCA, RCSB, PDBsum Function [Q0VBW0_MOUSE] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Phosphodiesterase 5 (PDE5) controls intracellular levels of cGMP through its regulation of cGMP hydrolysis. Hydrolytic activity of the C-terminal catalytic domain is increased by cGMP binding to the N-terminal GAF A domain. We present the NMR solution structure of the cGMP-bound PDE5A GAF A domain. The cGMP orientation in the buried binding pocket was defined through 37 intermolecular nuclear Overhauser effects. Comparison with GAF domains from PDE2A and adenylyl cyclase cyaB2 reveals a conserved overall domain fold of a six-stranded beta-sheet and four alpha-helices that form a well defined cGMP binding pocket. However, the nucleotide coordination is distinct with a series of altered binding contacts. The structure suggests that nucleotide binding specificity is provided by Asp-196, which is positioned to form two hydrogen bonds to the guanine ring of cGMP. An alanine mutation of Asp-196 disrupts cGMP binding and increases cAMP affinity in constructs containing only GAF A causing an altered cAMP-bound structural conformation. NMR studies on the tandem GAF domains reveal a flexible GAF A domain in the absence of cGMP, and indicate a large conformational change upon ligand binding. Furthermore, we identify a region of approximately 20 residues directly N-terminal of GAF A as critical for tight dimerization of the tandem GAF domains. The features of the PDE5 regulatory domain revealed here provide an initial structural basis for future investigations of the regulatory mechanism of PDE5 and the design of GAF-specific regulators of PDE5 function. Solution structure of the cGMP binding GAF domain from phosphodiesterase 5: insights into nucleotide specificity, dimerization, and cGMP-dependent conformational change.,Heikaus CC, Stout JR, Sekharan MR, Eakin CM, Rajagopal P, Brzovic PS, Beavo JA, Klevit RE J Biol Chem. 2008 Aug 15;283(33):22749-59. Epub 2008 Jun 4. PMID:18534985 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphodiesterase

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