3BMC
Structure of Pteridine Reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor (NADP+) and substrate (folate)
Summary for 3BMC
| Entry DOI | 10.2210/pdb3bmc/pdb |
| Related | 2C7V 3BMD 3BME 3BMF 3BMG 3BMH 3BMI 3BMJ 3BMK 3BML 3BMM 3BMN 3BMO 3BMQ 3BMR 3BMS 3BMT |
| Descriptor | Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, FOLIC ACID, ... (5 entities in total) |
| Functional Keywords | pteridine reductase, ptr1, trypanosoma brucei, short chain dehydrogenase, substrate, folate, oxidoreductase |
| Biological source | Trypanosoma brucei brucei More |
| Total number of polymer chains | 4 |
| Total formula weight | 127434.37 |
| Authors | Tulloch, L.B.,Hunter, W.N. (deposition date: 2007-12-13, release date: 2008-12-16, Last modification date: 2011-07-13) |
| 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 (2.6 Å) |
Structure validation
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