PDBsum entry 3uwp

Transferase

PDB id: 3uwp

Contents

Protein chain

341 a.a.

Ligands

5ID

UNX ×6

Metals

IOD ×2

_NA

Waters ×69

PDB id:

3uwp

Name:

Transferase

Title:

Crystal structure of dot1l in complex with 5-iodotubercidin

Structure:

Histone-lysine n-methyltransferase, h3 lysine-79 specific. Chain: a. Fragment: unp residues 1-420. Synonym: dot1-like protein, histone h3-k79 methyltransferase, h3-k79- hmtase, lysine n-methyltransferase 4. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dot1l, kiaa1814, kmt4. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.05Å R-factor: 0.196 R-free: 0.223

Authors:

W.Yu,W.Tempel,D.Smil,M.Schapira,Y.Li,M.Vedadi,K.T.Nguyen, A.K.Wernimont,C.H.Arrowsmith,A.M.Edwards,C.Bountra,J.Weigelt, P.J.Brown,Structural Genomics Consortium (Sgc)

Key ref:

W.Yu et al. (2012). Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun, 3, 1288. PubMed id: 23250418

Date:

02-Dec-11 Release date: 14-Mar-12

Protein chain

Q8TEK3  (DOT1L_HUMAN) -  Histone-lysine N-methyltransferase, H3 lysine-79 specific from Homo sapiens

Seq: 1537 a.a.

Struc: 341 a.a.

Enzyme reactions

• Enzyme class: E.C.2.1.1.360 - [histone H3]-lysine(79) N-trimethyltransferase.
• Reaction: L-lysyl₇₉-[histone H3] + 3 S-adenosyl-L-methionine = N₆,N₆,N₆- trimethyl-L-lysyl₇₉-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H⁺

L-lysyl(79)-[histone H3] + 3 × S-adenosyl-L-methionine = N(6),N(6),N(6)- trimethyl-L-lysyl(79)-[histone H3] + 3 × S-adenosyl-L-homocysteine + 3 × H(+) (Bound ligand (Het Group name = 5ID) matches with 58.62% similarity)

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

Added reference

Nat Commun 3:1288 (2012)

PubMed id: 23250418

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.

W.Yu, E.J.Chory, A.K.Wernimont, W.Tempel, A.Scopton, A.Federation, J.J.Marineau, J.Qi, D.Barsyte-Lovejoy, J.Yi, R.Marcellus, R.E.Iacob, J.R.Engen, C.Griffin, A.Aman, E.Wienholds, F.Li, J.Pineda, G.Estiu, T.Shatseva, T.Hajian, R.Al-Awar, J.E.Dick, M.Vedadi, P.J.Brown, C.H.Arrowsmith, J.E.Bradner, M.Schapira.

ABSTRACT

Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethionine-competitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.