1E7W

One active site, two modes of reduction correlate the mechanism of leishmania pteridine reductase with pterin metabolism and antifolate drug resistance in trpanosomes

Summary for 1E7W

• Entry DOI: 10.2210/pdb1e7w/pdb
• Descriptor: PTERIDINE REDUCTASE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, METHOTREXATE, ... (5 entities in total)
• Functional Keywords: dihydrofolate reductase, pteridine reductase, shortchain dehydrogenase, methotrexate resistance, oxidoreductase
• Biological source: LEISHMANIA MAJOR
• Total number of polymer chains: 2
• Total formula weight: 64031.62

Authors

Gourley, D.G.,Hunter, W.N. (deposition date: 2000-09-11, release date: 2001-09-06, Last modification date: 2024-05-08)

Primary citation

Gourley, D.G.,Schuttelkopf, A.,Leonard, G.,Luba, J.,Hardy, L.,Beverley, S.,Hunter, W.N.
Pteridine Reductase Mechanism Correlates Pterin Metabolism with Drug Resistance in Trypanosomatid Parasites.
Nat.Struct.Biol., 8:521-, 2001

PubMed Abstract: Pteridine reductase (PTR1) is a short-chain reductase (SDR) responsible for the salvage of pterins in parasitic trypanosomatids. PTR1 catalyzes the NADPH-dependent two-step reduction of oxidized pterins to the active tetrahydro-forms and reduces susceptibility to antifolates by alleviating dihydrofolate reductase (DHFR) inhibition. Crystal structures of PTR1 complexed with cofactor and 7,8-dihydrobiopterin (DHB) or methotrexate (MTX) delineate the enzyme mechanism, broad spectrum of activity and inhibition by substrate or an antifolate. PTR1 applies two distinct reductive mechanisms to substrates bound in one orientation. The first reduction uses the generic SDR mechanism, whereas the second shares similarities with the mechanism proposed for DHFR. Both DHB and MTX form extensive hydrogen bonding networks with NADP(H) but differ in the orientation of the pteridine.

PubMed: 11373620
DOI: 10.1038/88584

Experimental method

X-RAY DIFFRACTION (1.75 Å)