PDBsum entry 4clh

Oxidoreductase

PDB id: 4clh

Contents

Protein chains

252 a.a.

Ligands

NAP ×4

W8G ×8

ACT ×2

Waters ×718

PDB id:

4clh

Name:

Oxidoreductase

Title:

Crystal structure of pteridine reductase 1 (ptr1) from trypanosoma brucei in ternary complex with cofactor and inhibitor

Structure:

Pteridine reductase 1. Chain: a, b, c, d. Synonym: ptr1. Engineered: yes

Source:

Trypanosoma brucei brucei. Organism_taxid: 5702. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.85Å R-factor: 0.147 R-free: 0.193

Authors:

K.L.Barrack,W.N.Hunter

Key ref:

A.I.Khalaf et al. (2014). Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1. J Med Chem, 57, 6479-6494. PubMed id: 25007262 DOI: 10.1021/jm500483b

Date:

14-Jan-14 Release date: 21-Jan-15

Protein chains

O76290  (O76290_TRYBB) -  Pteridine reductase from Trypanosoma brucei brucei

Seq: 268 a.a.

Struc: 252 a.a.

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

DOI no: 10.1021/jm500483b

J Med Chem 57:6479-6494 (2014)

PubMed id: 25007262

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1.

A.I.Khalaf, J.K.Huggan, C.J.Suckling, C.L.Gibson, K.Stewart, F.Giordani, M.P.Barrett, P.E.Wong, K.L.Barrack, W.N.Hunter.

ABSTRACT

The treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp., has been identified as a candidate target, and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from Trypanosoma brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. Eight compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus, although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development.