PDBsum entry 4ai9

Oxidoreductase

PDB id: 4ai9

Contents

Protein chains

348 a.a.

Ligands

DZA ×3

GOL

Metals

_NI ×2

_ZN ×2

_CL ×2

Waters ×568

PDB id:

4ai9

Name:

Oxidoreductase

Title:

Jmjd2a complexed with daminozide

Structure:

Lysine-specific demethylase 4a. Chain: a, b. Fragment: catalytic domain, residues 1-359. Synonym: jmjc domain-containing histone demethylation protein 3a, jumonji domain-containing protein 2a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: r3.

Resolution:

2.25Å R-factor: 0.216 R-free: 0.237

Authors:

R.Chowdhury,C.J.Schofield

Key ref:

N.R.Rose et al. (2012). Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases. J Med Chem, 55, 6639-6643. PubMed id: 22724510

Date:

08-Feb-12 Release date: 03-Oct-12

Protein chains

O75164  (KDM4A_HUMAN) -  Lysine-specific demethylase 4A from Homo sapiens

Seq: 1064 a.a.

Struc: 348 a.a.

Enzyme reactions

• Enzyme class 2: E.C.1.14.11.66 - [histone H3]-trimethyl-L-lysine(9) demethylase.
• Reaction: N₆,N₆,N₆-trimethyl-L-lysyl₉-[histone H3] + 2 2-oxoglutarate + 2 O2 = N₆-methyl-L-lysyl₉-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2

N(6),N(6),N(6)-trimethyl-L-lysyl(9)-[histone H3] + 2 × 2-oxoglutarate + 2 × O2 = N(6)-methyl-L-lysyl(9)-[histone H3] + 2 × formaldehyde + 2 × succinate + 2 × CO2 (Bound ligand (Het Group name = DZA) matches with 58.33% similarity)

• Enzyme class 3: E.C.1.14.11.69 - [histone H3]-trimethyl-L-lysine(36) demethylase.
• Reaction: N₆,N₆,N₆-trimethyl-L-lysyl₃₆-[histone H3] + 2 2-oxoglutarate + 2 O2 = N₆-methyl-L-lysyl₃₆-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2

N(6),N(6),N(6)-trimethyl-L-lysyl(36)-[histone H3] + 2 × 2-oxoglutarate + 2 × O2 = N(6)-methyl-L-lysyl(36)-[histone H3] + 2 × formaldehyde + 2 × succinate + 2 × CO2 (Bound ligand (Het Group name = DZA) matches with 58.33% similarity)

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 Med Chem 55:6639-6643 (2012)

PubMed id: 22724510

Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases.

N.R.Rose, E.C.Woon, A.Tumber, L.J.Walport, R.Chowdhury, X.S.Li, O.N.King, C.Lejeune, S.S.Ng, T.Krojer, M.C.Chan, A.M.Rydzik, R.J.Hopkinson, K.H.Che, M.Daniel, C.Strain-Damerell, C.Gileadi, G.Kochan, I.K.Leung, J.Dunford, K.K.Yeoh, P.J.Ratcliffe, N.Burgess-Brown, F.von Delft, S.Muller, B.Marsden, P.E.Brennan, M.A.McDonough, U.Oppermann, R.J.Klose, C.J.Schofield, A.Kawamura.

ABSTRACT

The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.