Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Trypanosoma brucei UDP-galactose-4'-epimerase in ternary complex with NAD+ and the substrate analogue UDP-4-deoxy-4-fluoro-alpha-D-galactose
AU - Alphey, Magnus S.
AU - Burton, Andrew
AU - Urbaniak, Michael D.
AU - Boons, Geert-Jan
AU - Ferguson, Michael A. J.
AU - Hunter, William N.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - The structure of the NAD-dependent oxidoreductase UDP-galactose-4'-epimerase from Trypanosoma brucei in complex with cofactor and the substrate analogue UDP-4-deoxy-4-fluoro-alpha-D-galactose has been determined using diffraction data to 2.7 A resolution. Despite the high level of sequence and structure conservation between the trypanosomatid enzyme and those from humans, yeast and bacteria, the binding of the 4-fluoro-alpha-D-galactose moiety is distinct from previously reported structures. Of particular note is the observation that when bound to the T. brucei enzyme, the galactose moiety of this fluoro-derivative is rotated approximately 180 degrees with respect to the orientation of the hexose component of UDP-glucose when in complex with the human enzyme. The architecture of the catalytic centre is designed to effectively bind different orientations of the hexose, a finding that is consistent with a mechanism that requires the sugar to maintain a degree of flexibility within the active site.
AB - The structure of the NAD-dependent oxidoreductase UDP-galactose-4'-epimerase from Trypanosoma brucei in complex with cofactor and the substrate analogue UDP-4-deoxy-4-fluoro-alpha-D-galactose has been determined using diffraction data to 2.7 A resolution. Despite the high level of sequence and structure conservation between the trypanosomatid enzyme and those from humans, yeast and bacteria, the binding of the 4-fluoro-alpha-D-galactose moiety is distinct from previously reported structures. Of particular note is the observation that when bound to the T. brucei enzyme, the galactose moiety of this fluoro-derivative is rotated approximately 180 degrees with respect to the orientation of the hexose component of UDP-glucose when in complex with the human enzyme. The architecture of the catalytic centre is designed to effectively bind different orientations of the hexose, a finding that is consistent with a mechanism that requires the sugar to maintain a degree of flexibility within the active site.
KW - Animals
KW - Catalytic Domain
KW - Crystallography, X-Ray
KW - NAD
KW - Protein Structure, Secondary
KW - Substrate Specificity
KW - Trypanosoma brucei brucei
KW - UDPglucose 4-Epimerase
KW - Uridine Diphosphate Galactose
U2 - 10.1107/S1744309106028740
DO - 10.1107/S1744309106028740
M3 - Journal article
C2 - 16946458
VL - 62
SP - 829
EP - 834
JO - Acta Crystallographica Section F: Structural Biology and Crystallization Communications
JF - Acta Crystallographica Section F: Structural Biology and Crystallization Communications
IS - 9
ER -