5WQA

Crystal structure of PDE4D catalytic domain complexed with Selaginpulvilins K

Summary for 5WQA

• Entry DOI: 10.2210/pdb5wqa/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, 1-[2-(4-hydroxyphenyl)ethynyl]-9,9-bis(4-methoxyphenyl)-7-oxidanyl-fluorene-2-carbaldehyde, ZINC ION, ... (5 entities in total)
• Functional Keywords: natural pde4 inhibtor, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Apical cell membrane : Q08499
• Total number of polymer chains: 2
• Total formula weight: 78270.06

Authors

Huang, Y.,Zhang, T.,Zheng, X.,Yin, S.,Luo, H.B. (deposition date: 2016-11-24, release date: 2017-02-22, Last modification date: 2023-11-08)

Primary citation

Huang, Y.,Liu, X.,Wu, D.,Tang, G.,Lai, Z.,Zheng, X.,Yin, S.,Luo, H.B.
The discovery, complex crystal structure, and recognition mechanism of a novel natural PDE4 inhibitor from Selaginella pulvinata
Biochem. Pharmacol., 130:51-59, 2017

PubMed Abstract: Phosphodiesterase-4 (PDE4) is an important drug target for treatment of inflammation-related diseases. Till now, natural PDE4 inhibitors are rare and their co-crystal structures with PDE4 are hardly available. In the present study, selaginpulvilins K and L (1 and 2), two novel fluorene derivatives, were isolated from a traditional Chinese medicine Selaginella pulvinata and exhibited remarkable inhibition against phosphodiesterase-4D (PDE4D) at IC 11nM and 90nM, respectively. Compound 1 also showed a good selectivity across PDE families with the selective fold ranging from 30 to 909. To understand the recognition mechanism of selaginpulvilins towards PDE4, the crystal structure of PDE4D bound with 1 was successfully determined by the X-ray diffraction method and presented an unusual binding mode in which the stretched skeleton of the inhibitor bound shallowly to the active site but had interactions with multi sub-pockets, such as Q, HC, M, and S, especially strong interaction with the metal region. Assisted with molecular modeling, the structure-activity relationship and the selectivity of selaginpulvilins were also well explored, which would facilitate the future rational inhibitor design or structural optimizations.

PubMed: 28159622
DOI: 10.1016/j.bcp.2017.01.016

Experimental method

X-RAY DIFFRACTION (2.3 Å)