4BQH

Crystal structure of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei in complex with inhibitor

Summary for 4BQH

• Entry DOI: 10.2210/pdb4bqh/pdb
• Descriptor: UDP-N-ACETYLGLUCOSAMINE PYROPHOSPHORYLASE, SULFATE ION, (3S)-3-[2-(1,3-benzodioxol-5-yl)-2-oxidanylidene-ethyl]-4-bromanyl-5-methyl-3-oxidanyl-1H-indol-2-one, ... (4 entities in total)
• Functional Keywords: transferase, inhibitor
• Biological source: TRYPANOSOMA BRUCEI
• Total number of polymer chains: 1
• Total formula weight: 61195.09

Authors

Fang, W.,Raimi, O.G.,vanAalten, D.M.F. (deposition date: 2013-05-30, release date: 2013-07-17, Last modification date: 2024-10-16)

Primary citation

Urbaniak, M.D.,Collie, I.T.,Fang, W.,Aristotelous, T.,Eskilsson, S.,Raimi, O.G.,Harrison, J.,Hopkins Navratolova, I.,Frearson, J.A.,Van Aalten, D.M.F.,Ferguson, M.A.J.
A Novel Allosteric Inhibitor of the Uridine Diphosphate N-Acetylglucosamine Pyrophosphorylase from Trypanosoma Brucei.
Acs Chem.Biol., 8:1981-, 2013

PubMed Abstract: Uridine diphosphate N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the final reaction in the biosynthesis of UDP-GlcNAc, an essential metabolite in many organisms including Trypanosoma brucei, the etiological agent of Human African Trypanosomiasis. High-throughput screening of recombinant T. brucei UAP identified a UTP-competitive inhibitor with selectivity over the human counterpart despite the high level of conservation of active site residues. Biophysical characterization of the UAP enzyme kinetics revealed that the human and trypanosome enzymes both display a strictly ordered bi-bi mechanism, but with the order of substrate binding reversed. Structural characterization of the T. brucei UAP-inhibitor complex revealed that the inhibitor binds at an allosteric site absent in the human homologue that prevents the conformational rearrangement required to bind UTP. The identification of a selective inhibitory allosteric binding site in the parasite enzyme has therapeutic potential.

PubMed: 23834437
DOI: 10.1021/CB400411X

Experimental method

X-RAY DIFFRACTION (1.75 Å)