title: Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation.
abstract: BACKGROUND
  The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP) utilizing adenosine triphosphate (ATP) as the preferred phosphoryl donor.
  
  
  RESULTS
  Here, we present the first structures of Trypanosoma brucei rhodesiense adenosine kinase (TbrAK): the structure of TbrAK in complex with the bisubstrate inhibitor P(1),P(5)-di(adenosine-5')-pentaphosphate (AP5A) at 1.55 Å, and TbrAK complexed with the recently discovered activator 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (compound 1) at 2.8 Å resolution.
  
  
  CONCLUSIONS
  The structural details and their comparison give new insights into substrate and activator binding to TbrAK at the molecular level. Further structure-activity relationship analyses of a series of derivatives of compound 1 support the observed binding mode of the activator and provide a possible mechanism of action with respect to their activating effect towards TbrAK.
authors.affiliation: Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Lausanne, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kuettel
authors.forename: Jason
authors.initials: J
authors.lastname: Greenwald
authors.forename: Dirk
authors.initials: D
authors.lastname: Kostrewa
authors.forename: Shaheen
authors.initials: S
authors.lastname: Ahmed
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.forename: Remo
authors.initials: R
authors.lastname: Perozzo
mesh_terms: D000248:Adenosine Kinase / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D020536:Enzyme Activators / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D016833:Trypanosoma brucei rhodesiense / Q000737:chemistry / Q000201:enzymology*
chemical_list: D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D000248:Adenosine Kinase