PDBsum entry 4nw7

Hydrolase/hydrolase inhibitor

PDB id: 4nw7

Contents

Protein chain

344 a.a.

Ligands

2O5

EDO ×6

Metals

_ZN

_MG

_NA

Waters ×193

PDB id:

4nw7

Name:

Hydrolase/hydrolase inhibitor

Title:

Pde4 catalytic domain

Structure:

Camp-specific 3',5'-cyclic phosphodiesterase 4b. Chain: a. Fragment: unp residues 324-691. Synonym: dpde4, pde32. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dpde4, pde4, pde4b. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: sf9.

Resolution:

2.15Å R-factor: 0.158 R-free: 0.207

Authors:

D.Fox Iii,T.E.Edwards

Key ref:

T.J.Hagen et al. (2014). Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Bioorg Med Chem Lett, 24, 4031-4034. PubMed id: 24998378 DOI: 10.1016/j.bmcl.2014.06.002

Date:

05-Dec-13 Release date: 15-Oct-14

Protein chain

Q07343  (PDE4B_HUMAN) -  3',5'-cyclic-AMP phosphodiesterase 4B from Homo sapiens

Seq: 736 a.a.

Struc: 344 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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: 10.1016/j.bmcl.2014.06.002

Bioorg Med Chem Lett 24:4031-4034 (2014)

PubMed id: 24998378

Discovery of triazines as selective PDE4B versus PDE4D inhibitors.

T.J.Hagen, X.Mo, A.B.Burgin, D.Fox, Z.Zhang, M.E.Gurney.

ABSTRACT

In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.