5WH5
Crystal structure of the PDE4D2 catalytic domain in complex with inhibitor (R)-Zl-n-91
Summary for 5WH5
| Entry DOI | 10.2210/pdb5wh5/pdb |
| Descriptor | cAMP-specific 3',5'-cyclic phosphodiesterase 4D, 1-[4-(difluoromethoxy)-3-{[(3R)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one, ZINC ION, ... (5 entities in total) |
| Functional Keywords | phosphodiesterase, inhibitors, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 76245.83 |
| Authors | Wang, H. (deposition date: 2017-07-14, release date: 2018-07-18, Last modification date: 2024-03-13) |
| Primary citation | Feng, X.,Wang, H.,Ye, M.,Xu, X.T.,Xu, Y.,Yang, W.,Zhang, H.T.,Song, G.,Ke, H. Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors. Biochemistry, 57:4518-4525, 2018 Cited by PubMed Abstract: Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors. PubMed: 29975048DOI: 10.1021/acs.biochem.8b00336 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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