High-resolution crystal structure of Trypanosoma brucei UDP-galactose 4'-epimerase: a potential target for structure-based development of novel trypanocides.
The crystal structure of UDP-galactose 4'-epimerase from the protozoan parasite Trypanosoma brucei in complex with the cofactor NAD(+) and a fragment of the substrates, UDP, has been determined at 2.0 A resolution (1 A = 0.1 nm). This enzyme, recently proven to be essential for this pathogenic parasite, shares 33% sequence identity with the corresponding enzyme in the human host. Structural comparisons indicate that many of the protein-ligand interactions are conserved between the two enzymes. However, in the UDP-binding pocket there is a non-conservative substitution from Gly237 in the human enzyme to Cys266 in the T. brucei enzyme. Such a significant difference could be exploited by the structure-based design of selective inhibitors using the structure of the trypanosomatid enzyme as a template.
Shaw
Matthew P
MP
Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Bond
Charles S
CS
Roper
Janine R
JR
Gourley
David G
DG
Ferguson
Michael A J
MA
Hunter
William N
WN
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D014344:Trypanocidal Agents / Q000138:chemical synthesis*; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014534:UDPglucose 4-Epimerase / Q000737:chemistry*
D014344:Trypanocidal Agents; D014534:UDPglucose 4-Epimerase