High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A

Function

Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes. Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP. Specifically regulates natriuretic-peptide-dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart. Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein (Probable). In brain, involved in cognitive function, such as learning and long-term memory (By similarity).

Classification

Family (Pfam)

PF00233 PDEase_I

InterPro

HD/PDEase_dom, PDEase, PDEase_catalytic_dom, PDEase_catalytic_dom_sf, PDEase_CS

Functional cluster

Serine/Threonine Protein Kinases

Experimental structures · PDB · 25

• 2HD1 X-ray 2.23A
• 2YY2 X-ray 2.80A
• 3DY8 X-ray 2.15A
• 3DYL X-ray 2.70A
• 3DYN X-ray 2.10A
• 3DYQ X-ray 2.50A
• 3DYS X-ray 2.30A
• 3JSI X-ray 2.72A
• 3JSW X-ray 2.30A
• 3K3E X-ray 2.70A
• 3K3H X-ray 2.50A
• 3N3Z X-ray 2.75A
• … and 13 more

A predicted model is available from AlphaFold.

Gene Ontology · 20

• GO:0005829 cytosol
• GO:0005783 endoplasmic reticulum
• GO:0005794 Golgi apparatus
• GO:0043204 perikaryon
• GO:0048471 perinuclear region of cytoplasm
• GO:0005886 plasma membrane
• GO:0032587 ruffle membrane
• GO:0042383 sarcolemma
• GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity
• GO:0047555 3',5'-cyclic-GMP phosphodiesterase activity
• GO:0004114 3',5'-cyclic-nucleotide phosphodiesterase activity
• GO:0042802 identical protein binding
• GO:0046872 metal ion binding
• GO:0046069 cGMP catabolic process
• GO:0046068 cGMP metabolic process
• GO:0141162 negative regulation of cAMP/PKA signal transduction
• GO:2000178 negative regulation of neural precursor cell proliferation
• GO:0010613 positive regulation of cardiac muscle hypertrophy
• GO:1900273 positive regulation of long-term synaptic potentiation
• GO:0007165 signal transduction

Drugs targeting this protein · 6

• EDELINONTRINE inhibitor
• OSORESNONTRINE inhibitor
• TOVINONTRINE inhibitor
• IRSENONTRINE inhibitor
• PENTOXIFYLLINE inhibitor
• DIPYRIDAMOLE inhibitor

Related proteins · sequence + function similarity

• High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A 1.00
• High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A 0.96
• High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A 0.96
• High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A 0.75
• Probable 3',5'-cyclic phosphodiesterase pde-2 0.73
• High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A 0.73
• 3',5'-cyclic-AMP phosphodiesterase 4D 0.71
• 3',5'-cyclic-AMP phosphodiesterase 4B 0.71
• 3',5'-cyclic-AMP phosphodiesterase 4B 0.71
• 3',5'-cyclic-AMP phosphodiesterase 4D 0.70
• 3',5'-cyclic-AMP phosphodiesterase 4D 0.70
• Probable 3',5'-cyclic phosphodiesterase pde-1 0.70

Co-cited proteins · studied together in the literature

• High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A 3 shared papers
• High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A 1 shared papers
• cGMP-specific 3',5'-cyclic phosphodiesterase 1 shared papers

Literature · 19 cited papers

• Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature · 2015
• Phosphodiesterase 9: insights from protein structure and role in therapeutics. Life Sci. · 2014
• Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors. J. Med. Chem. · 2012
• Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design. J. Med. Chem. · 2012
• Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo. J. Pharmacol. Exp. Ther. · 2012
• Structural asymmetry of phosphodiesterase-9, potential protonation of a glutamic acid, and role of the invariant glutamine. PLoS ONE · 2011
• Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis. J. Med. Chem. · 2010
• Identification of a brain penetrant PDE9A inhibitor utilizing prospective design and chemical enablement as a rapid lead optimization strategy. J. Med. Chem. · 2009
• Structural basis for the catalytic mechanism of human phosphodiesterase 9. Proc. Natl. Acad. Sci. U.S.A. · 2008
• Specific use of start codons and cellular localization of splice variants of human phosphodiesterase 9A gene. BMC Mol. Biol. · 2006
• Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Mol. Pharmacol. · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• … and 7 more in the literature graph