PDBsum entry 4jht

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4jht

Contents

Protein chain

201 a.a.

Ligands

8XQ

ACT

DMS

Metals

_MN

Waters ×269

PDB id:

4jht

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Crystal structure of alkb in complex with 5-carboxy-8-hydroxyquinoline (iox1)

Structure:

Alpha-ketoglutarate-dependent dioxygenase alkb. Chain: a. Fragment: unp residues 12-216. Synonym: alkylated DNA repair protein alkb, DNA oxidative demethylase alkb. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 83333. Strain: k12. Gene: aidd, alkb, b2212, jw2200. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.18Å R-factor: 0.159 R-free: 0.166

Authors:

W.S.Aik,M.A.Mcdonough,C.J.Schofield

Key ref:

R.J.Hopkinson et al. (2013). 5-Carboxy-8-hydroxyquinoline is a Broad Spectrum 2-Oxoglutarate Oxygenase Inhibitor which Causes Iron Translocation. Chem Sci, 4, 3110-3117. PubMed id: 26682036

Date:

05-Mar-13 Release date: 26-Jun-13

Protein chain

P05050  (ALKB_ECOLI) -  Alpha-ketoglutarate-dependent dioxygenase AlkB from Escherichia coli (strain K12)

Seq: 216 a.a.

Struc: 201 a.a.

Enzyme reactions

• Enzyme class: E.C.1.14.11.33 - Dna oxidative demethylase.
• Reaction: a methylated nucleobase within DNA + 2-oxoglutarate + O2 = a nucleobase within DNA + formaldehyde + succinate + CO2

methylated nucleobase within DNA (Bound ligand (Het Group name = 8XQ) matches with 50.00% similarity) + 2-oxoglutarate + O2 = nucleobase within DNA + formaldehyde (Bound ligand (Het Group name = ACT) matches with 75.00% similarity) + succinate + CO2

• Cofactor: Fe cation

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

reference

Chem Sci 4:3110-3117 (2013)

PubMed id: 26682036

5-Carboxy-8-hydroxyquinoline is a Broad Spectrum 2-Oxoglutarate Oxygenase Inhibitor which Causes Iron Translocation.

R.J.Hopkinson, A.Tumber, C.Yapp, R.Chowdhury, W.Aik, K.H.Che, X.S.Li, J.B.L.Kristensen, O.N.F.King, M.C.Chan, K.K.Yeoh, H.Choi, L.J.Walport, C.C.Thinnes, J.T.Bush, C.Lejeune, A.M.Rydzik, N.R.Rose, E.A.Bagg, M.A.McDonough, T.Krojer, W.W.Yue, S.S.Ng, L.Olsen, P.E.Brennan, U.Oppermann, S.Muller-Knapp, R.J.Klose, P.J.Ratcliffe, C.J.Schofield, A.Kawamura.

ABSTRACT

2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors,N-oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and γ-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement.