5WQA

Crystal structure of PDE4D catalytic domain complexed with Selaginpulvilins K


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.219 

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This is version 1.3 of the entry. See complete history


Literature

The discovery, complex crystal structure, and recognition mechanism of a novel natural PDE4 inhibitor from Selaginella pulvinata

Huang, Y.Liu, X.Wu, D.Tang, G.Lai, Z.Zheng, X.Yin, S.Luo, H.B.

(2017) Biochem Pharmacol 130: 51-59

  • DOI: https://doi.org/10.1016/j.bcp.2017.01.016
  • Primary Citation of Related Structures:  
    5WQA

  • 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 50 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.


  • Organizational Affiliation

    School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP-specific 3',5'-cyclic phosphodiesterase 4D
A, B
334Homo sapiensMutation(s): 0 
Gene Names: PDE4DDPDE3
EC: 3.1.4.53
UniProt & NIH Common Fund Data Resources
Find proteins for Q08499 (Homo sapiens)
Explore Q08499 
Go to UniProtKB:  Q08499
PHAROS:  Q08499
GTEx:  ENSG00000113448 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08499
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.219 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 57.992α = 90
b = 80.784β = 90
c = 163.575γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CrysalisProdata reduction
CrysalisProdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of ChinaChina21572279
National High Technology Research and Development Program of ChinaChina2015AA020928

Revision History  (Full details and data files)

  • Version 1.0: 2017-02-22
    Type: Initial release
  • Version 1.1: 2017-04-05
    Changes: Database references
  • Version 1.2: 2017-10-18
    Changes: Author supporting evidence
  • Version 1.3: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description