6PF3
Crystal structure of human thymidylate synthase Delta (7-29) in complex with dUMP and 2-(4-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)benzamido)-4-chlorobenzoic acid
Summary for 6PF3
| Entry DOI | 10.2210/pdb6pf3/pdb |
| Descriptor | Thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, 2-({4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzene-1-carbonyl}amino)-4-chlorobenzoic acid, ... (4 entities in total) |
| Functional Keywords | inhibitor, ts, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 135740.35 |
| Authors | Czyzyk, D.J.,Valhondo, M.,Jorgensen, W.L.,Anderson, K.S. (deposition date: 2019-06-21, release date: 2019-10-02, Last modification date: 2023-10-11) |
| Primary citation | Czyzyk, D.J.,Valhondo, M.,Deiana, L.,Tirado-Rives, J.,Jorgensen, W.L.,Anderson, K.S. Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors. Eur.J.Med.Chem., 183:111673-111673, 2019 Cited by PubMed Abstract: Cryptosporidiosis is a human gastrointestinal disease caused by protozoans of the genus Cryptosporidium, which can be fatal in immunocompromised individuals. The essential enzyme, thymidylate synthase (TS), is responsible for de novo synthesis of deoxythymidine monophosphate. The TS active site is relatively conserved between Cryptosporidium and human enzymes. In previous work, we identified compound 1, (2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidin-methyl-phenyl-l-glutamic acid), as a promising selective Cryptosporidium hominis TS (ChTS) inhibitor. In the present study, we explore the structure-activity relationship around 1 glutamate moiety by synthesizing and biochemically evaluating the inhibitory activity of analogues against ChTS and human TS (hTS). X-Ray crystal structures were obtained for compounds bound to both ChTS and hTS. We establish the importance of the 2-phenylacetic acid moiety methylene linker in optimally positioning compounds 23, 24, and 25 within the active site. Moreover, through the comparison of structural data for 5, 14, 15, and 23 bound in both ChTS and hTS identified that active site rigidity is a driving force in determining inhibitor selectivity. PubMed: 31536894DOI: 10.1016/j.ejmech.2019.111673 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.391 Å) |
Structure validation
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