PDBsum entry 3jq7

Oxidoreductase

PDB id: 3jq7

Contents

Protein chains

249 a.a. *

Ligands

NAP ×4

DX2 ×4

ACT ×2

DTT

Waters ×611

* Residue conservation analysis

PDB id:

3jq7

Name:

Oxidoreductase

Title:

Crystal structure of pteridine reductase 1 (ptr1) from trypanosoma brucei in ternary complex with cofactor (NADP+) and inhibitor 6- phenylpteridine-2,4,7-triamine (dx2)

Structure:

Pteridine reductase 1. Chain: a, c, d. Fragment: unp residues 102-369. Engineered: yes. Pteridine reductase 1. Chain: b. Fragment: unp residues 102-369. Engineered: yes

Source:

Trypanosoma brucei. Organism_taxid: 5691. Gene: ptr1, tb927.8.2210. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.80Å R-factor: 0.154 R-free: 0.191

Authors:

L.B.Tulloch,W.N.Hunter

Key ref:

L.B.Tulloch et al. (2010). Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases. J Med Chem, 53, 221-229. PubMed id: 19916554

Date:

06-Sep-09 Release date: 08-Dec-09

Supersedes:

3bme

Protein chains

Q581W1  (Q581W1_TRYB2) -  Pteridine reductase, putative from Trypanosoma brucei brucei (strain 927/4 GUTat10.1)

Seq: 369 a.a.

Struc: 249 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.1.5.1.33 - pteridine reductase.
• Reaction: (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + 2 NADP⁺ = L-erythro- biopterin + 2 NADPH + 2 H⁺

(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + 2 × NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = L-erythro- biopterin + 2 × NADPH + 2 × H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

J Med Chem 53:221-229 (2010)

PubMed id: 19916554

Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases.

L.B.Tulloch, V.P.Martini, J.Iulek, J.K.Huggan, J.H.Lee, C.L.Gibson, T.K.Smith, C.J.Suckling, W.N.Hunter.

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.