PDBsum entry 1w0c

Oxidoreductase

PDB id: 1w0c

Contents

Protein chains

276 a.a. *

256 a.a. *

Ligands

NAP ×8

TAQ ×9

Waters ×1117

* Residue conservation analysis

PDB id:

1w0c

Name:

Oxidoreductase

Title:

Inhibition of leishmania major pteridine reductase (ptr1) by 2,4,6- triaminoquinazoline; structure of the NADP ternary complex.

Structure:

Pteridine reductase. Chain: a, b, c, d, e, f, g, h. Synonym: h region methotrexate resistance protein. Engineered: yes. Other_details: contains inhibitor taq

Source:

Leishmania major. Organism_taxid: 5664. Strain: b834. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.60Å R-factor: 0.267 R-free: 0.337

Authors:

K.Mcluskey,F.Gibellini,P.Carvalho,M.Avery,W.Hunter

Key ref:

K.McLuskey et al. (2004). Inhibition of Leishmania major pteridine reductase by 2,4,6-triaminoquinazoline: structure of the NADPH ternary complex. Acta Crystallogr D Biol Crystallogr, 60, 1780-1785. PubMed id: 15388924 DOI: 10.1107/S0907444904018955

Date:

02-Jun-04 Release date: 30-Sep-04

Protein chains

Q01782  (PTR1_LEIMA) -  Pteridine reductase 1 from Leishmania major

Seq: 288 a.a.

Struc: 276 a.a.*

Protein chains

Q01782  (PTR1_LEIMA) -  Pteridine reductase 1 from Leishmania major

Seq: 288 a.a.

Struc: 256 a.a.*

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

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E, F, G, H: 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

DOI no: 10.1107/S0907444904018955

Acta Crystallogr D Biol Crystallogr 60:1780-1785 (2004)

PubMed id: 15388924

Inhibition of Leishmania major pteridine reductase by 2,4,6-triaminoquinazoline: structure of the NADPH ternary complex.

K.McLuskey, F.Gibellini, P.Carvalho, M.A.Avery, W.N.Hunter.

ABSTRACT

The structure of Leishmania major pteridine reductase (PTR1) in complex with NADPH and the inhibitor 2,4,6-triaminoquinazoline (TAQ) has been solved in a new crystal form by molecular replacement and refined to 2.6 A resolution. The inhibitor mimics a fragment, the pterin head group, of the archetypal antifolate drug methotrexate (MTX) and exploits similar chemical features to bind in the PTR1 active site. Despite being a much smaller molecule, TAQ displays a similar inhibition constant to that of MTX. PTR1 is a target for the development of improved therapies for infections caused by trypanosomatid parasites and this analysis provides information to assist the structure-based development of novel enzyme inhibitors.

Selected figure(s)

Figure 3.
Figure 3 The active-site cleft of PTR1. The surface of subunit A is shown in grey, the surface of subunit B in green and Arg287' from subunit D in blue. The cofactor and inhibitor are represented in stick mode and coloured according to atom type: N, blue; O, red; P, pink; C, yellow for NADPH and black for TAQ. Selected residues that line the active-site cleft are labelled. Figs. 3, 4 and 5 were prepared with PyMOL (DeLano, 2002[100] [DeLano, W. L. (2002). The PyMOL Molecular Graphics System. DeLano Scientific, San Carlos, CA, USA.]-[101][bluearr.gif] ).

Figure 4.
Figure 4 Hydrogen-bonding interactions at the site of inhibition. A similar colour scheme to Figs. 2 and 3 is adopted; in addition, water molecules are depicted as marine-coloured spheres. Marine dashed lines represent possible hydrogen-bonding associations and a red dashed line represents the C-H [107][\cdots] O interaction between C5 (*) and the carbonyl of Gly225.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2004, 60, 1780-1785) copyright 2004.

Figures were selected by the author.