| Structural highlights
3h4v is a 8 chain structure with sequence from Leima. This structure supersedes the now removed PDB entry 2p8k. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 2qhx, 2bf7, 2bfm, 2bfa, 1w0c, 1e92, 1p33 |
| Gene: | PTR1, HMTXR (LEIMA) |
| Activity: | Pteridine reductase, with EC number 1.5.1.33 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[PTR1_LEIMA] Exhibits a NADPH-dependent biopterin reductase activity. Has good activity with folate and significant activity with dihydrofolate and dihydrobiopterin, but not with quinonoid dihydrobiopterin. Confers resistance to methotrexate (MTX).[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound 6a displayed a K(i) of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds. A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved K(i) (37 nM) against LmPTR1, and the structure of this complex was also determined. Biological evaluation of selected inhibitors was performed against the extracellular forms of T. cruzi and L. major, both wild-type and overexpressing PTR1 lines, as a model for PTR1-driven antifolate drug resistance and the intracellular form of T. cruzi. An additive profile was observed when PTR1 inhibitors were used in combination with known DHFR inhibitors, and a reduction in toxicity of treatment was observed with respect to administration of a DHFR inhibitor alone. The successful combination of antifolates targeting two enzymes indicates high potential for such an approach in the development of previously undescribed antiparasitic drugs.
Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development.,Cavazzuti A, Paglietti G, Hunter WN, Gamarro F, Piras S, Loriga M, Allecca S, Corona P, McLuskey K, Tulloch L, Gibellini F, Ferrari S, Costi MP Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1448-53. Epub 2008 Feb 1. PMID:18245389[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bello AR, Nare B, Freedman D, Hardy L, Beverley SM. PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11442-6. PMID:7972081
- ↑ Cavazzuti A, Paglietti G, Hunter WN, Gamarro F, Piras S, Loriga M, Allecca S, Corona P, McLuskey K, Tulloch L, Gibellini F, Ferrari S, Costi MP. Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1448-53. Epub 2008 Feb 1. PMID:18245389
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