PDBsum entry 1ro9

Hydrolase

PDB id: 1ro9

Contents

Protein chains

338 a.a. *

Ligands

8BR ×2

Metals

_ZN ×4

Waters ×263

* Residue conservation analysis

PDB id:

1ro9

Name:

Hydrolase

Title:

Crystal structures of the catalytic domain of phosphodiesterase 4b2b complexed with 8-br-amp

Structure:

Camp-specific 3',5'-cyclic phosphodiesterase 4b. Chain: a, b. Fragment: catalytic domain. Synonym: dpde4, pde32. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde4b. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469

Biol. unit:

Dimer (from PQS)

Resolution:

2.13Å R-factor: 0.210 R-free: 0.234

Authors:

R.X.Xu,W.J.Rocque,M.H.Lambert,D.E.Vanderwall,R.T.Nolte

Key ref:

R.X.Xu et al. (2004). Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol, 337, 355-365. PubMed id: 15003452 DOI: 10.1016/j.jmb.2004.01.040

Date:

01-Dec-03 Release date: 07-Dec-04

Protein chains

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

Seq: 736 a.a.

Struc: 338 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⁺

3',5'-cyclic AMP + H2O = AMP (Bound ligand (Het Group name = 8BR) matches with 95.83% similarity) + H(+)

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

Added reference

DOI no: 10.1016/j.jmb.2004.01.040

J Mol Biol 337:355-365 (2004)

PubMed id: 15003452

Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram.

R.X.Xu, W.J.Rocque, M.H.Lambert, D.E.Vanderwall, M.A.Luther, R.T.Nolte.

ABSTRACT

Phosphodiesterase catalyzes the hydrolysis of the intracellular second messenger 3',5'-cyclic AMP (cAMP) into the corresponding 5'-nucleotide. Phosphodiesterase 4 (PDE4), the major cAMP-specific PDE in inflammatory and immune cells, is an attractive target for the treatment of asthma and COPD. We have determined crystal structures of the catalytic domain of PDE4B complexed with AMP (2.0 A), 8-Br-AMP (2.13 A) and the potent inhibitor rolipram (2.0 A). All the ligands bind in the same hydrophobic pocket and can interact directly with the active site metal ions. The identity of these metal ions was examined using X-ray anomalous difference data. The structure of the AMP complex confirms the location of the catalytic site and allowed us to speculate about the detailed mechanism of catalysis. The high-resolution structures provided the experimental insight into the nucleotide selectivity of phosphodiesterase. 8-Br-AMP binds in the syn conformation to the enzyme and demonstrates an alternative nucleotide-binding mode. Rolipram occupies much of the AMP-binding site and forms two hydrogen bonds with Gln443 similar to the nucleotides.

Selected figure(s)

Figure 7.
Figure 7. Binding of 8-Br-AMP in the PDE4B active site. The protein backbone is shown as a gray ribbon. The Br is colored dark red. The carbon atoms of 8-Br-AMP are colored yellow, the phosphate is colored pink. The carbon atoms of important side-chain of the protein are shown in green. The metal ions are shown as yellow balls. The hydrogen bonds between protein and 8-Br-AMP are shown as white dotted lines. The protein interactions with metal ions are shown as cyan dotted lines.

Figure 8.
Figure 8. Comparison of the AMP and 8-Br-AMP bound to PDE4B. Schematic representation of the ligand-binding mode for each molecule including the major hydrogen bond interactions seen between each ligand and the active site.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2004, 337, 355-365) copyright 2004.

Figures were selected by an automated process.