PDBsum entry 3k5k

Transferase

PDB id: 3k5k

Contents

Protein chain

272 a.a. *

Ligands

SAH ×2

DXQ ×2

UNX ×2

Metals

_ZN ×8

_CL ×4

Waters ×459

* Residue conservation analysis

PDB id:

3k5k

Name:

Transferase

Title:

Discovery of a 2,4-diamino-7-aminoalkoxy-quinazoline as a potent inhibitor of histone lysine methyltransferase, g9a

Structure:

Histone-lysine n-methyltransferase, h3 lysine-9 specific 3. Chain: a, b. Fragment: unp residues 913-1193, set domain. Synonym: protein g9a, histone h3-k9 methyltransferase 3, h3-k9-hmtase 3, euchromatic histone-lysine n-methyltransferase 2, hla-b-associated transcript 8, lysine n-methyltransferase 1c. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ehmt2, bat8, c6orf30, g9a, kmt1c, ng36. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.70Å R-factor: 0.211 R-free: 0.264

Authors:

A.Dong,G.A.Wasney,F.Liu,X.Chen,A.Allali-Hassani,G.Senisterra,I.Chau, C.Bountra,J.Weigelt,A.M.Edwards,C.H.Arrowsmith,S.V.Frye,A.Bochkarev, P.J.Brown,J.Jin,M.Vedadi,Structural Genomics Consortium (Sgc)

Key ref:

F.Liu et al. (2009). Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J Med Chem, 52, 7950-7953. PubMed id: 19891491

Date:

07-Oct-09 Release date: 10-Nov-09

Protein chains

Q96KQ7  (EHMT2_HUMAN) -  Histone-lysine N-methyltransferase EHMT2 from Homo sapiens

Seq: 1210 a.a.

Struc: 272 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.1.1.- - ?????
• Enzyme class 3: E.C.2.1.1.367 - [histone H3]-lysine(9) N-methyltransferase.
• Reaction: L-lysyl₉-[histone H3] + S-adenosyl-L-methionine = N₆-methyl-L- lysyl₉-[histone H3] + S-adenosyl-L-homocysteine + H⁺

L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L- lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (Bound ligand (Het Group name = SAH) corresponds exactly)

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

Added reference

J Med Chem 52:7950-7953 (2009)

PubMed id: 19891491

Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a.

F.Liu, X.Chen, A.Allali-Hassani, A.M.Quinn, G.A.Wasney, A.Dong, D.Barsyte, I.Kozieradzki, G.Senisterra, I.Chau, A.Siarheyeva, D.B.Kireev, A.Jadhav, J.M.Herold, S.V.Frye, C.H.Arrowsmith, P.J.Brown, A.Simeonov, M.Vedadi, J.Jin.

ABSTRACT

SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.