3QI3

Crystal structure of PDE9A(Q453E) in complex with inhibitor BAY73-6691

Summary for 3QI3

• Entry DOI: 10.2210/pdb3qi3/pdb
• Related: 3QI4
• Descriptor: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, 1-(2-chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, ZINC ION, ... (5 entities in total)
• Functional Keywords: mutation, glutamine switch, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 124473.01

Authors

Hou, J.,Xu, J.,Liu, M.,Zhao, R.,Lou, H.,Ke, H. (deposition date: 2011-01-26, release date: 2011-04-27, Last modification date: 2024-02-21)

Primary citation

Hou, J.,Xu, J.,Liu, M.,Zhao, R.,Luo, H.B.,Ke, H.
Structural asymmetry of phosphodiesterase-9, potential protonation of a glutamic Acid, and role of the invariant glutamine.
Plos One, 6:e18092-e18092, 2011

PubMed Abstract: PDE9 inhibitors show potential for treatment of diseases such as diabetes. To help with discovery of PDE9 inhibitors, we performed mutagenesis, kinetic, crystallographic, and molecular dynamics analyses on the active site residues of Gln453 and its stabilizing partner Glu406. The crystal structures of the PDE9 Q453E mutant (PDE9Q453E) in complex with inhibitors IBMX and (S)-BAY73-6691 showed asymmetric binding of the inhibitors in two subunits of the PDE9Q453E dimer and also the significant positional change of the M-loop at the active site. The kinetic analysis of the Q453E and E406A mutants suggested that the invariant glutamine is critical for binding of substrates and inhibitors, but is unlikely to play a key role in the differentiation between substrates of cGMP and cAMP. The molecular dynamics simulations suggest that residue Glu406 may be protonated and may thus explain the hydrogen bond distance between two side chain oxygens of Glu453 and Glu406 in the crystal structure of the PDE9Q453E mutant. The information from these studies may be useful for design of PDE9 inhibitors.

PubMed: 21483814
DOI: 10.1371/journal.pone.0018092

Experimental method

X-RAY DIFFRACTION (2.3 Å)