4I15

Crystal structure of TbrPDEB1

Summary for 4I15

• Entry DOI: 10.2210/pdb4i15/pdb
• Descriptor: Class 1 phosphodiesterase PDEB1, ZINC ION, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: parasite pde, sleeping sickness, african trypanosomiasis, hydrolase
• Biological source: Trypanosoma brucei
• Total number of polymer chains: 2
• Total formula weight: 77628.00

Authors

Wang, H.,Ke, H. (deposition date: 2012-11-20, release date: 2013-03-13, Last modification date: 2024-02-28)

Primary citation

Jansen, C.,Wang, H.,Kooistra, A.J.,de Graaf, C.,Orrling, K.M.,Tenor, H.,Seebeck, T.,Bailey, D.,de Esch, I.J.,Ke, H.,Leurs, R.
Discovery of Novel Trypanosoma brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure.
J.Med.Chem., 56:2087-2096, 2013

PubMed Abstract: Trypanosoma brucei cyclic nucleotide phosphodiesterase B1 (TbrPDEB1) and TbrPDEB2 have recently been validated as new therapeutic targets for human African trypanosomiasis by both genetic and pharmacological means. In this study we report the crystal structure of the catalytic domain of the unliganded TbrPDEB1 and its use for the in silico screening for new TbrPDEB1 inhibitors with novel scaffolds. The TbrPDEB1 crystal structure shows the characteristic folds of human PDE enzymes but also contains the parasite-specific P-pocket found in the structures of Leishmania major PDEB1 and Trypanosoma cruzi PDEC. The unliganded TbrPDEB1 X-ray structure was subjected to a structure-based in silico screening approach that combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method. This approach identified six novel TbrPDEB1 inhibitors with IC50 values of 10-80 μM, which may be further optimized as potential selective TbrPDEB inhibitors.

PubMed: 23409953
DOI: 10.1021/jm3017877

Experimental method

X-RAY DIFFRACTION (1.65 Å)