title: Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase.
abstract: The 1.8 A resolution de novo structure of nucleoside 2-deoxyribosyltransferase (EC 2.4.2.6) from Trypanosoma brucei (TbNDRT) has been determined by SADa phasing in an unliganded state and several ligand-bound states. This enzyme is important in the salvage pathway of nucleoside recycling. To identify novel lead compounds, we exploited "fragment cocktail soaks". Out of 304 compounds tried in 31 cocktails, four compounds could be identified crystallographically in the active site. In addition, we demonstrated that very short soaks of approximately 10 s are sufficient even for rather hydrophobic ligands to bind in the active site groove, which is promising for the application of similar soaking experiments to less robust crystals of other proteins.
authors.affiliation: Department of Biochemistry, Division of Infectious Disease, and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bosch
authors.forename: Mark A
authors.initials: MA
authors.lastname: Robien
authors.forename: Christopher
authors.initials: C
authors.lastname: Mehlin
authors.forename: Erica
authors.initials: E
authors.lastname: Boni
authors.forename: Aaron
authors.initials: A
authors.lastname: Riechers
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Myler
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Worthey
authors.forename: George
authors.initials: G
authors.lastname: DeTitta
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Luft
authors.forename: Angela
authors.initials: A
authors.lastname: Lauricella
authors.forename: Stacey
authors.initials: S
authors.lastname: Gulde
authors.forename: Lori A
authors.initials: LA
authors.lastname: Anderson
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Kalyuzhniy
authors.forename: Helen M
authors.initials: HM
authors.lastname: Neely
authors.forename: Jenni
authors.initials: J
authors.lastname: Ross
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Earnest
authors.forename: Michael
authors.initials: M
authors.lastname: Soltis
authors.forename: Lori
authors.initials: L
authors.lastname: Schoenfeld
authors.forename: Frank
authors.initials: F
authors.lastname: Zucker
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Merritt
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Wim G J
authors.initials: WG
authors.lastname: Hol
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001592:Benzyl Alcohols / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*
chemical_list: D001592:Benzyl Alcohols; D007211:Indoles; D007546:Isoquinolines; D008024:Ligands; D011804:Quinolines; D014344:Trypanocidal Agents; D010430:Pentosyltransferases; C021888:nucleoside deoxyribosyltransferase