TY - JOUR
T1 - The crystal structure of ATP-bound phosphofructokinase from Trypanosoma brucei reveals conformational transitions different from those of other phosphofructokinases
AU - McNae, Iain W
AU - Martinez-Oyanedel, José
AU - Keillor, Jeffrey W
AU - Michels, Paul
AU - Fothergill-Gilmore, Linda A
AU - Walkinshaw, Malcolm D
PY - 2009/2
Y1 - 2009/2
N2 - The crystal structure of the ATP-bound form of the tetrameric phosphofructokinase (PFK) from Trypanosoma brucei enables detailed comparisons to be made with the structures of the apoenzyme form of the same enzyme, as well as with those of bacterial ATP-dependent and PP(i)-dependent PFKs. The active site of T. brucei PFK (which is strictly ATP-dependent but belongs to the PP(i)-dependent family by sequence similarities) is a chimera of the two types of PFK. In particular, the active site of T. brucei PFK possesses amino acid residues and structural features characteristic of both types of PFK. Conformational changes upon ATP binding are observed that include the opening of the active site to accommodate the two substrates, MgATP and fructose 6-phosphate, and a dramatic ordering of the C-terminal helices, which act like reaching arms to hold the tetramer together. These conformational transitions are fundamentally different from those of other ATP-dependent PFKs. The substantial differences in structure and mechanism of T. brucei PFK compared with bacterial and mammalian PFKs give optimism for the discovery of species-specific drugs for the treatment of diseases caused by protist parasites of the trypanosomatid family.
AB - The crystal structure of the ATP-bound form of the tetrameric phosphofructokinase (PFK) from Trypanosoma brucei enables detailed comparisons to be made with the structures of the apoenzyme form of the same enzyme, as well as with those of bacterial ATP-dependent and PP(i)-dependent PFKs. The active site of T. brucei PFK (which is strictly ATP-dependent but belongs to the PP(i)-dependent family by sequence similarities) is a chimera of the two types of PFK. In particular, the active site of T. brucei PFK possesses amino acid residues and structural features characteristic of both types of PFK. Conformational changes upon ATP binding are observed that include the opening of the active site to accommodate the two substrates, MgATP and fructose 6-phosphate, and a dramatic ordering of the C-terminal helices, which act like reaching arms to hold the tetramer together. These conformational transitions are fundamentally different from those of other ATP-dependent PFKs. The substantial differences in structure and mechanism of T. brucei PFK compared with bacterial and mammalian PFKs give optimism for the discovery of species-specific drugs for the treatment of diseases caused by protist parasites of the trypanosomatid family.
KW - phosphofructokinase
KW - trypanosomes
KW - X-ray crystallography
KW - allostery
KW - eukaryote
UR - http://www.scopus.com/inward/record.url?scp=58849160333&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2008.11.047
DO - 10.1016/j.jmb.2008.11.047
M3 - Article
C2 - 19084537
VL - 385
SP - 1519
EP - 1533
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 5
ER -