3K3H

Crystal structure of the PDE9A catalytic domain in complex with (S)-BAY73-6691

Summary for 3K3H

• Entry DOI: 10.2210/pdb3k3h/pdb
• Related: 3K3E
• Descriptor: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde9, catalytic domain, cgmp, hydrolase, manganese, metal-binding, phosphoprotein
• Biological source: Homo sapiens (human)
• Cellular location: Isoform PDE9A1: Cell projection, ruffle membrane. Isoform PDE9A2: Cell projection, ruffle membrane. Isoform PDE9A3: Cytoplasm. Isoform PDE9A17: Cytoplasm: O76083
• Total number of polymer chains: 2
• Total formula weight: 77986.03

Authors

Wang, H.,Luo, X.,Ye, M.,Hou, J.,Robinson, H.,Ke, H. (deposition date: 2009-10-02, release date: 2010-02-16, Last modification date: 2024-10-09)

Primary citation

Wang, H.,Luo, X.,Ye, M.,Hou, J.,Robinson, H.,Ke, H.
Insight into Binding of Phosphodiesterase-9A Selective Inhibitors by Crystal Structures and Mutagenesis
J.Med.Chem., 53:1726-1731, 2010

PubMed Abstract: PDE9 inhibitors have been studied as therapeutics for treatment of cardiovascular diseases, diabetes, and neurodegenerative disorders. To illustrate the inhibitor selectivity, the crystal structures of the PDE9A catalytic domain in complex with the enantiomers of PDE9 inhibitor 1-(2-chlorophenyl)-6-(3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine-4(5H)-one ((R)-BAY73-6691 or (S)-BAY73-6691, 1r or 1s) were determined and mutagenesis was performed. The structures showed that the fluoromethyl groups of 1r and 1s had different orientations while the other parts of the inhibitors commonly interacted with PDE9A. These differences may explain the slightly different affinity of 1r (IC(50) = 22 nM) and 1s (IC(50) = 88 nM). The mutagenesis experiments revealed that contribution of the binding residues to the inhibitor sensitivity varies dramatically, from few-fold to 3 orders of magnitude. On the basis of the crystal structures, a hypothesized compound that simulates the recently published PDE9 inhibitors was modeled to provide insight into the inhibitor selectivity.

PubMed: 20121115
DOI: 10.1021/jm901519f

Experimental method

X-RAY DIFFRACTION (2.5 Å)