PDBsum entry 4y8c

Hydrolase/hydrolase inhibitor

PDB id: 4y8c

Contents

Protein chains

322 a.a.

Ligands

49D ×2

Metals

_MG ×2

_ZN ×2

Waters ×12

PDB id:

4y8c

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of phosphodiesterase 9 in complex with (s)-c33

Structure:

High affinity cgmp-specific 3',5'-cyclic phosphodiesterase 9a. Chain: a, b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde9a. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693

Resolution:

2.70Å R-factor: 0.207 R-free: 0.231

Authors:

M.Huang

Key ref:

M.Huang et al. (2015). Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor. Mol Pharmacol, 88, 836-845. PubMed id: 26316540 DOI: 10.1124/mol.115.099747

Date:

16-Feb-15 Release date: 16-Sep-15

Protein chains

O76083  (PDE9A_HUMAN) -  High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A from Homo sapiens

Seq: 593 a.a.

Struc: 322 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.4.35 - 3',5'-cyclic-GMP phosphodiesterase.
• Reaction: 3',5'-cyclic GMP + H2O = GMP + H⁺

3',5'-cyclic GMP (Bound ligand (Het Group name = 49D) matches with 41.18% similarity) + H2O = GMP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1124/mol.115.099747

Mol Pharmacol 88:836-845 (2015)

PubMed id: 26316540

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.

M.Huang, Y.Shao, J.Hou, W.Cui, B.Liang, Y.Huang, Z.Li, Y.Wu, X.Zhu, P.Liu, Y.Wan, H.Ke, H.B.Luo.

ABSTRACT

Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.