3HY3
Structure of human MTHFS with 10-formyltetrahydrofolate
Summary for 3HY3
| Entry DOI | 10.2210/pdb3hy3/pdb |
| Related | 3HXT 3HY4 3HY6 |
| Descriptor | 5-formyltetrahydrofolate cyclo-ligase, N-({4-[{[(2R,4S,4aR,6S,8aS)-2-amino-4-hydroxydecahydropteridin-6-yl]methyl}(formyl)amino]phenyl}carbonyl)-D-glutamic acid, NICKEL (II) ION, ... (5 entities in total) |
| Functional Keywords | antifolate, cancer, 10-formyltetrahydrofolate, atp-binding, folate-binding, ligase, magnesium, nucleotide-binding |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm: P49914 |
| Total number of polymer chains | 1 |
| Total formula weight | 24105.31 |
| Authors | |
| Primary citation | Wu, D.,Li, Y.,Song, G.,Cheng, C.,Zhang, R.,Joachimiak, A.,Shaw, N.,Liu, Z.-J. Structural basis for the inhibition of human 5,10-methenyltetrahydrofolate synthetase by N10-substituted folate analogues Cancer Res., 69:7294-7301, 2009 Cited by PubMed Abstract: 5,10-Methenyltetrahydrofolate synthetase (MTHFS) regulates the flow of carbon through the one-carbon metabolic network, which supplies essential components for the growth and proliferation of cells. Inhibition of MTHFS in human MCF-7 breast cancer cells has been shown to arrest the growth of cells. Absence of the three-dimensional structure of human MTHFS (hMTHFS) has hampered the rational design and optimization of drug candidates. Here, we report the structures of native hMTHFS, a binary complex of hMTHFS with ADP, hMTHFS bound with the N5-iminium phosphate reaction intermediate, and an enzyme-product complex of hMTHFS. The N5-iminium phosphate captured for the first time in our crystal structure unravels a unique strategy used by hMTHFS for recognition of the substrate and provides structural basis for the regulation of enzyme activity. Binding of N10-substituted folate analogues places Y152 in the middle of the channel connecting ATP binding site with the substrate binding pocket, precluding the positioning of gamma-phosphate for a nucleophilic attack. Using the structures of hMTHFS as a guide, we have probed the role of residues surrounding the active site in catalysis by mutagenesis. The ensemble of hMTHFS structures and the mutagenesis data yield a coherent picture of the MTHFS active site, determinants of substrate specificity, and new insights into the mechanism of inhibition of hMTHFS. PubMed: 19738041DOI: 10.1158/0008-5472.CAN-09-1927 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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