PDBsum entry 5izc

Oxidoreductase

PDB id: 5izc

Contents

Protein chains

249 a.a.

Ligands

NAP ×4

6F4 ×4

ACT ×3

GOL

Waters ×573

PDB id:

5izc

Name:

Oxidoreductase

Title:

Trypanosoma brucei ptr1 in complex with inhibitor f032

Structure:

Pteridine reductase. Chain: a, b, d. Engineered: yes. Other_details: only in subunit c cys60 has been oxidized to ocs. In all subunits cys168 has been chemically modified by bme. Pteridine reductase. Chain: c. Engineered: yes. Other_details: only in subunit c cys60 has been oxidized to ocs. In

Source:

Trypanosoma brucei brucei. Organism_taxid: 5702. Gene: ptr1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_taxid: 469008

Resolution:

1.92Å R-factor: 0.163 R-free: 0.206

Authors:

C.Pozzi,G.Landi,F.Di Pisa,S.Mangani

Key ref:

P.Linciano et al. (2017). Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To InhibitTrypanosoma bruceiPteridine Reductase in Support of Early-Stage Drug Discovery. ACS Omega, 2, 5666-5683. PubMed id: 28983525

Date:

25-Mar-16 Release date: 05-Apr-17

Protein chains

O76290  (O76290_TRYBB) -  Pteridine reductase from Trypanosoma brucei brucei

Seq: 268 a.a.

Struc: 249 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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

ACS Omega 2:5666-5683 (2017)

PubMed id: 28983525

Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To InhibitTrypanosoma bruceiPteridine Reductase in Support of Early-Stage Drug Discovery.

P.Linciano, A.Dawson, I.Pöhner, D.M.Costa, M.S.Sá, A.Cordeiro-da-Silva, R.Luciani, S.Gul, G.Witt, B.Ellinger, M.Kuzikov, P.Gribbon, J.Reinshagen, M.Wolf, B.Behrens, V.Hannaert, P.A.M.Michels, E.Nerini, C.Pozzi, F.di Pisa, G.Landi, N.Santarem, S.Ferrari, P.Saxena, S.Lazzari, G.Cannazza, L.H.Freitas-Junior, C.B.Moraes, B.S.Pascoalino, L.M.Alcântara, C.P.Bertolacini, V.Fontana, U.Wittig, W.Müller, R.C.Wade, W.N.Hunter, S.Mangani, L.Costantino, M.P.Costi.

ABSTRACT

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors ofLeishmania majorPTR1 for activity againstTrypanosoma brucei(Tb). We solved crystal structures of severalTbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors ofTbPTR1 with low toxicity. In particular, compound4m, a biphenyl-thiadiazole-2,5-diamine with IC₅₀= 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC₅₀value. In addition, the antiparasitic activity of the combination of4mand MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. bruceiagents can be obtained.