PDBsum entry 4gh6

Hydrolase/hydrolase inhibitor

PDB id: 4gh6

Contents

Protein chain

326 a.a.

Ligands

LUO ×3

Metals

_MG ×2

_ZN ×2

Waters ×18

PDB id:

4gh6

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of the pde9a catalytic domain in complex with inhibitor 28

Structure:

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

Source:

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

Resolution:

2.70Å R-factor: 0.212 R-free: 0.245

Authors:

J.Hou,H.Ke

Key ref:

F.Meng et al. (2012). Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design. J Med Chem, 55, 8549-8558. PubMed id: 22985069

Date:

07-Aug-12 Release date: 03-Oct-12

Protein chains

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

Seq: 593 a.a.

Struc: 326 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 55:8549-8558 (2012)

PubMed id: 22985069

Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design.

F.Meng, J.Hou, Y.X.Shao, P.Y.Wu, M.Huang, X.Zhu, Y.Cai, Z.Li, J.Xu, P.Liu, H.B.Luo, Y.Wan, H.Ke.

ABSTRACT

A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC(50) of 21 nM and 3.3 μM, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.