PDBsum entry 2zzc

Oxidoreductase

PDB id: 2zzc

Contents

Protein chains

485 a.a. *

Ligands

FAD ×4

NAP ×4

Waters ×897

* Residue conservation analysis

PDB id:

2zzc

Name:

Oxidoreductase

Title:

Crystal structure of NADP(h):human thioredoxin reductase i

Structure:

Thioredoxin reductase 1, cytoplasmic. Chain: a, b, c, d. Fragment: residues (-13)-499. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: txnrd1, kdrf. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.60Å R-factor: 0.211 R-free: 0.260

Authors:

Y.C.Lo,T.P.Ko,A.H.J.Wang

Key ref:

Y.C.Lo et al. (2009). Terpyridine-platinum(II) complexes are effective inhibitors of mammalian topoisomerases and human thioredoxin reductase 1. J Inorg Biochem, 103, 1082-1092. PubMed id: 19525010

Date:

09-Feb-09 Release date: 18-Aug-09

Protein chains

Q16881  (TRXR1_HUMAN) -  Thioredoxin reductase 1, cytoplasmic from Homo sapiens

Seq: 649 a.a.

Struc: 485 a.a.

Enzyme reactions

• Enzyme class 2: E.C.1.11.1.2 - Nadph peroxidase.
• Reaction: H2O2 + NADPH + H⁺ = NADP⁺ + 2 H2O

H2O2 + NADPH + H(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = NADP(+) + 2 × H2O

• Enzyme class 3: E.C.1.8.1.9 - thioredoxin-disulfide reductase (NADPH).
• Reaction: [thioredoxin]-dithiol + NADP⁺ = [thioredoxin]-disulfide + NADPH + H⁺

[thioredoxin]-dithiol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = [thioredoxin]-disulfide + NADPH + 2 × H(+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

J Inorg Biochem 103:1082-1092 (2009)

PubMed id: 19525010

Terpyridine-platinum(II) complexes are effective inhibitors of mammalian topoisomerases and human thioredoxin reductase 1.

Y.C.Lo, T.P.Ko, W.C.Su, T.L.Su, A.H.Wang.

ABSTRACT

Terpyridine-platinum(II) (TP-Pt(II)) complexes are known to possess DNA-intercalating activity and have been regarded as potential antitumor agents. However, their cytotoxic mechanism remains unclear. To investigate the possible mechanism, a series of TP-Pt(II) compounds were prepared and their biological activities assessed. The DNA binding activities of the aromatic thiolato[TP-Pt(II)] complexes were stronger than the aliphatic 2-hydroxylethanethiolato(2,2':6',2''-terpyridine)platinum(II) [TP(HET)]. TP-Pt(II) complexes inhibited topoisomerase IIalpha or topoisomerase I activity at IC(50) values of about 5 microM and 10-20 microM, respectively, whereas the human thioredoxin reductase 1 (hTrxR1) activity was inhibited with IC(50) values in the range of 58-78 nM. At the cellular level, they possessed cytotoxicity with IC(50) values between 7 and 19 microM against HeLa cells. Additionally, using X-ray crystallography and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, we elucidated that the TP-Pt(II) complexes inhibited hTrxR1 activity by blocking its C-terminal active-site selenocysteine. Therefore, TP-Pt(II) complexes possess inhibitory activities against multiple biological targets, and they may be further studied as anticancer agents.