PDBsum entry 3k3h

Hydrolase

PDB id: 3k3h

Contents

Protein chain

321 a.a. *

Ligands

BYE ×2

Metals

_ZN ×2

_MG ×2

Waters ×16

* Residue conservation analysis

PDB id:

3k3h

Name:

Hydrolase

Title:

Crystal structure of the pde9a catalytic domain in complex with (s)- bay73-6691

Structure:

High affinity cgmp-specific 3',5'-cyclic phosphodiesterase 9a. Chain: a, b. Fragment: catalytic domain: unp residues 241-566. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde9a, pde9a2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.50Å R-factor: 0.223 R-free: 0.245

Authors:

H.Wang,X.Luo,M.Ye,J.Hou,H.Robinson,H.Ke

Key ref:

H.Wang et al. (2010). Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis. J Med Chem, 53, 1726-1731. PubMed id: 20121115

Date:

02-Oct-09 Release date: 16-Feb-10

Protein chains

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

Seq: 593 a.a.

Struc: 321 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⁺

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

Added reference

J Med Chem 53:1726-1731 (2010)

PubMed id: 20121115

Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis.

H.Wang, X.Luo, M.Ye, J.Hou, H.Robinson, H.Ke.

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.