PDBsum entry 6fdc

Hydrolase

PDB id: 6fdc

Contents

Protein chains

329 a.a.

Ligands

EDO ×2

DD5

D5N

Metals

_ZN ×2

_MG ×5

Waters ×504

PDB id:

6fdc

Name:

Hydrolase

Title:

Crystal structure of the pde4d catalytic domain in complex with gebr- 32a

Structure:

Camp-specific 3',5'-cyclic phosphodiesterase 4d. Chain: a, b. Synonym: dpde3,pde43. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde4d, dpde3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

1.45Å R-factor: 0.179 R-free: 0.199

Authors:

T.Prosdocimi,S.Donini,E.Parisini

Key ref:

T.Prosdocimi et al. (2018). Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds. Biochemistry, 57, 2876-2888. PubMed id: 29652483 DOI: 10.1021/acs.biochem.8b00288

Date:

22-Dec-17 Release date: 16-May-18

Protein chains

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

Seq: 809 a.a.

Struc: 329 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

DOI no: 10.1021/acs.biochem.8b00288

Biochemistry 57:2876-2888 (2018)

PubMed id: 29652483

Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds.

T.Prosdocimi, L.Mollica, S.Donini, M.S.Semrau, A.P.Lucarelli, E.Aiolfi, A.Cavalli, P.Storici, S.Alfei, C.Brullo, O.Bruno, E.Parisini.

ABSTRACT

Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure-activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms.