3JQ8
Crystal structure of pteridine reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor (NADP+) and inhibitor 6,7,7-trimethyl-7,8-dihydropteridine-2,4-diamine (DX3)
Replaces: 3BMFSummary for 3JQ8
| Entry DOI | 10.2210/pdb3jq8/pdb |
| Related | 3JQ6 3JQ7 3JQ9 3JQA 3JQB 3JQC 3JQD 3JQE 3JQF 3JQG |
| Descriptor | Pteridine reductase 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6,7,7-trimethyl-7,8-dihydropteridine-2,4-diamine, ... (6 entities in total) |
| Functional Keywords | pteridine reductase, ptr1, trypanosoma brucei, short chain dehydrogenase, inhibitor, oxidoreductase |
| Biological source | Trypanosoma brucei More |
| Total number of polymer chains | 4 |
| Total formula weight | 126680.01 |
| Authors | Tulloch, L.B.,Hunter, W.N. (deposition date: 2009-09-06, release date: 2009-12-08, Last modification date: 2023-09-06) |
| Primary citation | Tulloch, L.B.,Martini, V.P.,Iulek, J.,Huggan, J.K.,Lee, J.H.,Gibson, C.L.,Smith, T.K.,Suckling, C.J.,Hunter, W.N. Structure-based design of pteridine reductase inhibitors targeting african sleeping sickness and the leishmaniases. J.Med.Chem., 53:221-229, 2010 Cited by PubMed Abstract: Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness. PubMed: 19916554DOI: 10.1021/jm901059x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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