PDBsum entry 5f3c

Oxidoreductase

PDB id: 5f3c

Contents

Protein chains

343 a.a.

Ligands

5U8 ×4

DMS ×11

GOL

Metals

_CL

_ZN ×8

Waters ×1041

PDB id:

5f3c

Name:

Oxidoreductase

Title:

Crystal structure of human kdm4a in complex with compound 52d

Structure:

Lysine-specific demethylase 4a. Chain: a, b, c, d. Fragment: unp 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. Gene: kdm4a, jhdm3a, jmjd2, jmjd2a, kiaa0677. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: rosetta 2.

Resolution:

2.06Å R-factor: 0.162 R-free: 0.196

Authors:

Y.-V.Le Bihan,I.M.Westwood,R.L.M.Van Montfort

Key ref:

V.Bavetsias et al. (2016). 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors. J Med Chem, 59, 1388-1409. PubMed id: 26741168 DOI: 10.1021/acs.jmedchem.5b01635

Date:

02-Dec-15 Release date: 20-Jan-16

Protein chains

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

Seq: 1064 a.a.

Struc: 343 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] (Bound ligand (Het Group name = GOL) matches with 45.45% similarity) + 2 × 2-oxoglutarate + 2 × O2 = N(6)-methyl-L-lysyl(9)-[histone H3] + 2 × formaldehyde + 2 × succinate + 2 × CO2

• 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] (Bound ligand (Het Group name = GOL) matches with 45.45% similarity) + 2 × 2-oxoglutarate + 2 × O2 = N(6)-methyl-L-lysyl(36)-[histone H3] + 2 × formaldehyde + 2 × succinate + 2 × CO2

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

DOI no: 10.1021/acs.jmedchem.5b01635

J Med Chem 59:1388-1409 (2016)

PubMed id: 26741168

8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.

V.Bavetsias, R.M.Lanigan, G.F.Ruda, B.Atrash, M.G.McLaughlin, A.Tumber, N.Y.Mok, Y.V.Le Bihan, S.Dempster, K.J.Boxall, F.Jeganathan, S.B.Hatch, P.Savitsky, S.Velupillai, T.Krojer, K.S.England, J.Sejberg, C.Thai, A.Donovan, A.Pal, G.Scozzafava, J.M.Bennett, A.Kawamura, C.Johansson, A.Szykowska, C.Gileadi, N.A.Burgess-Brown, F.von Delft, U.Oppermann, Z.Walters, J.Shipley, F.I.Raynaud, S.M.Westaway, R.K.Prinjha, O.Fedorov, R.Burke, C.J.Schofield, I.M.Westwood, C.Bountra, S.Müller, R.L.van Montfort, P.E.Brennan, J.Blagg.

ABSTRACT

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.