Premium
The crystal structure of a bacterial, bifunctional 5, 10 methylene‐tetrahydrofolate dehydrogenase/cyclohydrolase
Author(s) -
Shen Betty W.,
Dyer David H.,
Huang JieYu,
D'Ari Linda,
Rabinowitz Jesse,
Stoddard Barry L.
Publication year - 1999
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.8.6.1342
Subject(s) - chemistry , bifunctional , phosphofructokinase 2 , methylene , dehydrogenase , biochemistry , stereochemistry , enzyme , medicinal chemistry , catalysis
The structure of a bifunctional 5, 10‐methylene‐tetrahydrofolate dehydrogenase/cyclohydrolase from Escherichia coli has been determined at 2.5 Å resolution in the absence of bound substrates and compared to the NADP‐bound structure of the homologous enzyme domains from a trifunctional human synthetase enzyme. Superposition of these structures allows the identification of a highly conserved cluster of basic residues that are appropriately positioned to serve as a binding site for the poly‐γ‐glutamyl tail of the tetrahydrofolate substrate. Modeling studies and molecular dynamic simulations of bound methylene‐tetrahydrofolate and NADP shows that this binding site would allow interaction of the nicotinamide and pterin rings in the dehydrogenase active site. Comparison of these enzymes also indicates differences between their active sites that might allow the development of inhibitors specific to the bacterial target.