title: The molecular dynamics of Trypanosoma brucei UDP-galactose 4'-epimerase: a drug target for African sleeping sickness.
abstract: During the past century, several epidemics of human African trypanosomiasis, a deadly disease caused by the protist Trypanosoma brucei, have afflicted sub-Saharan Africa. Over 10 000 new victims are reported each year, with hundreds of thousands more at risk. As current drug treatments are either highly toxic or ineffective, novel trypanocides are urgently needed. The T. brucei galactose synthesis pathway is one potential therapeutic target. Although galactose is essential for T. brucei survival, the parasite lacks the transporters required to intake galactose from the environment. UDP-galactose 4'-epimerase (TbGalE) is responsible for the epimerization of UDP-glucose to UDP-galactose and is therefore of great interest to medicinal chemists. Using molecular dynamics simulations, we investigate the atomistic motions of TbGalE in both the apo and holo states. The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom. This dependence provides important insights into TbGalE function and may help guide future computer-aided drug discovery efforts targeting this protein.
authors.affiliation: Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093-0365, USA. a1friedm@ucsd.edu
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Friedman
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Durrant
authors.forename: Levi C T
authors.initials: LC
authors.lastname: Pierce
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McCorvie
authors.forename: David J
authors.initials: DJ
authors.lastname: Timson
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D014346:Trypanosoma brucei brucei / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000469:parasitology*; D014534:UDPglucose 4-Epimerase / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D014534:UDPglucose 4-Epimerase