PDBsum entry 2qyn

Hydrolase

PDB id: 2qyn

Contents

Protein chains

326 a.a. *

Ligands

NPV ×2

Metals

_MG ×2

_ZN ×2

Waters ×365

* Residue conservation analysis

PDB id:

2qyn

Name:

Hydrolase

Title:

Crystal structure of pde4d2 in complex with inhibitor npv

Structure:

Camp-specific 3',5'-cyclic phosphodiesterase 4d. Chain: a, b. Fragment: the catalytic domain of pde4d2 with residues 86-413. Synonym: dpde3, pde43. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde4d, dpde3. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

1.57Å R-factor: 0.225 R-free: 0.248

Authors:

H.Ke

Key ref:

H.Wang et al. (2007). Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J, 408, 193-201. PubMed id: 17727341

Date:

15-Aug-07 Release date: 08-Apr-08

Protein chains

Q08499  (PDE4D_HUMAN) -  3',5'-cyclic-AMP phosphodiesterase 4D from Homo sapiens

Seq: 809 a.a.

Struc: 326 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.4.53 - 3',5'-cyclic-AMP phosphodiesterase.
• Reaction: 3',5'-cyclic AMP + H2O = AMP + H⁺

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

Added reference

Biochem J 408:193-201 (2007)

PubMed id: 17727341

Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors.

H.Wang, M.S.Peng, Y.Chen, J.Geng, H.Robinson, M.D.Houslay, J.Cai, H.Ke.

ABSTRACT

PDE4 (phosphodiesterase-4)-selective inhibitors have attracted much attention as potential therapeutics for the treatment of both depression and major inflammatory diseases, but their practical application has been compromised by side effects. A possible cause for the side effects is that current PDE4-selective inhibitors similarly inhibit isoforms from all four PDE4 subfamilies. The development of PDE4 subfamily-selective inhibitors has been hampered by a lack of structural information. In the present study, we rectify this by providing the crystal structures of the catalytic domains of PDE4A, PDE4B and PDE4D in complex with the PDE4 inhibitor NVP {4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid} as well as the unliganded PDE4C structure. NVP binds in the same conformation to the deep cAMP substrate pocket and interacts with the same residues in each instance. However, detailed structural comparison reveals significant conformational differences. Although the active sites of PDE4B and PDE4D are mostly comparable, PDE4A shows significant displacements of the residues next to the invariant glutamine residue that is critical for substrate and inhibitor binding. PDE4C appears to be more distal from other PDE4 subfamilies, with certain key residues being disordered. Our analyses provide the first structural basis for the development of PDE4 subfamily-selective inhibitors.