4I75

Crystal structure of the Trypanosoma brucei Inosine-Adenosine-Guanosine nucleoside hydrolase in complex with the NiTris metalorganic complex

Summary for 4I75

• Entry DOI: 10.2210/pdb4i75/pdb
• Related: 3EPW 3FZ0 4I70 4I71 4I72 4I73 4I74
• Descriptor: Inosine-adenosine-guanosine-nucleoside hydrolase, CALCIUM ION, NICKEL (II) ION, ... (5 entities in total)
• Functional Keywords: nucleoside hydrolase, open (alpha, beta) structure, nh fold, hydrolase
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 2
• Total formula weight: 73554.27

Authors

Giannese, F.,Degano, M. (deposition date: 2012-11-30, release date: 2013-08-07, Last modification date: 2024-04-03)

Primary citation

Giannese, F.,Berg, M.,Van der Veken, P.,Castagna, V.,Tornaghi, P.,Augustyns, K.,Degano, M.
Structures of purine nucleosidase from Trypanosoma brucei bound to isozyme-specific trypanocidals and a novel metalorganic inhibitor
Acta Crystallogr.,Sect.D, 69:1553-1566, 2013

PubMed Abstract: Sleeping sickness is a deadly disease that primarily affects sub-Saharan Africa and is caused by protozoan parasites of the Trypanosoma genus. Trypanosomes are purine auxotrophs and their uptake pathway has long been appreciated as an attractive target for drug design. Recently, one tight-binding competitive inhibitor of the trypanosomal purine-specific nucleoside hydrolase (IAGNH) showed remarkable trypanocidal activity in a murine model of infection. Here, the enzymatic characterization of T. brucei brucei IAGNH is presented, together with its high-resolution structures in the unliganded form and in complexes with different inhibitors, including the trypanocidal compound UAMC-00363. A description of the crucial contacts that account for the high-affinity inhibition of IAGNH by iminoribitol-based compounds is provided and the molecular mechanism underlying the conformational change necessary for enzymatic catalysis is identified. It is demonstrated for the first time that metalorganic complexes can compete for binding at the active site of nucleoside hydrolase enzymes, mimicking the positively charged transition state of the enzymatic reaction. Moreover, we show that divalent metal ions can act as noncompetitive IAGNH inhibitors, stabilizing a nonproductive conformation of the catalytic loop. These results open a path for rational improvement of the potency and the selectivity of existing compounds and suggest new scaffolds that may be used as blueprints for the design of novel antitrypanosomal compounds.

PubMed: 23897478
DOI: 10.1107/S0907444913010792

Experimental method

X-RAY DIFFRACTION (1.8 Å)