2FM0

Crystal structure of PDE4D in complex with L-869298

Summary for 2FM0

• Entry DOI: 10.2210/pdb2fm0/pdb
• Related: 2FM5
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde. enantiomer binding, inhibitor selectivity, camp signalling, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): Q08499
• Total number of polymer chains: 4
• Total formula weight: 168736.21

Authors

Huai, Q.,Sun, Y.,Wang, H.,Macdonald, D.,Aspiotis, R.,Robinson, H.,Huang, Z.,Ke, H. (deposition date: 2006-01-06, release date: 2006-03-28, Last modification date: 2024-04-03)

Primary citation

Huai, Q.,Sun, Y.,Wang, H.,Macdonald, D.,Aspiotis, R.,Robinson, H.,Huang, Z.,Ke, H.
Enantiomer Discrimination Illustrated by the High Resolution Crystal Structures of Type 4 Phosphodiesterase
J.Med.Chem., 49:1867-1873, 2006

PubMed Abstract: Type 4 phosphodiesterase (PDE4) inhibitors are emerging as new treatments for a number of disorders including asthma and chronic obstructive pulmonary disease. Here we report the biochemical characterization on the second generation inhibitor (+)-1 (L-, IC50=0.4 nM) and its enantiomer (-)-1 (L-, IC50=43 nM) and their cocrystal structures with PDE4D at 2.0 A resolution. Despite the 107-fold affinity difference, both enantiomers interact with the same sets of residues in the rigid active site. The weaker (-)-1 adopts an unfavorable conformation to preserve the pivotal interactions between the Mg-bound waters and the N-oxide of pyridine. These structures support a model in which inhibitors are anchored by the invariant glutamine at one end and the metal-pocket residues at another end. This model provides explanations for most of the observed structure-activity relationship and the metal ion dependency of the catechol-ether based inhibitors and should facilitate their further design.

PubMed: 16539372
DOI: 10.1021/jm051273d

Experimental method

X-RAY DIFFRACTION (2 Å)