PDBsum entry 4i15

Hydrolase

PDB id: 4i15

Contents

Protein chains

333 a.a.

Metals

_MG ×2

_ZN ×2

Waters ×404

PDB id:

4i15

Name:

Hydrolase

Title:

Crystal structure of tbrpdeb1

Structure:

Class 1 phosphodiesterase pdeb1. Chain: a, b. Fragment: catalytic domain (unp residues 576-918). Synonym: phosphodiesterase b1. Engineered: yes

Source:

Trypanosoma brucei. Organism_taxid: 5691. Gene: pdeb1. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

1.65Å R-factor: 0.204 R-free: 0.223

Authors:

H.Wang,H.Ke

Key ref:

C.Jansen et al. (2013). Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure. J Med Chem, 56, 2087-2096. PubMed id: 23409953 DOI: 10.1021/jm3017877

Date:

20-Nov-12 Release date: 13-Mar-13

Protein chains

Q8WQX9  (Q8WQX9_9TRYP) -  Phosphodiesterase from Trypanosoma brucei

Seq: 930 a.a.

Struc: 333 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.4.- - ?????

DOI no: 10.1021/jm3017877

J Med Chem 56:2087-2096 (2013)

PubMed id: 23409953

Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure.

C.Jansen, H.Wang, A.J.Kooistra, C.de Graaf, K.M.Orrling, H.Tenor, T.Seebeck, D.Bailey, I.J.de Esch, H.Ke, R.Leurs.

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.