4ER3

Crystal Structure of Human DOT1L in complex with inhibitor EPZ004777

Summary for 4ER3

• Entry DOI: 10.2210/pdb4er3/pdb
• Related: 4EQZ 4ER0 4ER5 4ER6 4ER7
• Descriptor: Histone-lysine N-methyltransferase, H3 lysine-79 specific, 7-{5-[(3-{[(4-tert-butylphenyl)carbamoyl]amino}propyl)(propan-2-yl)amino]-5-deoxy-beta-D-ribofuranosyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, SULFATE ION, ... (6 entities in total)
• Functional Keywords: histone, methyltransferase, epigenetics, transferase-transferase inhibitor complex, structural genomics, structural genomics consortium, sgc, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : Q8TEK3
• Total number of polymer chains: 1
• Total formula weight: 41952.40

Authors

Wernimont, A.K.,Tempel, W.,Yu, W.,Scopton, A.,Li, Y.,Nguyen, K.T.,Federation, A.,Marineau, J.,Qi, J.,Vedadi, M.,Bradner, J.E.,Schapira, M.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Brown, P.J.,Structural Genomics Consortium (SGC) (deposition date: 2012-04-19, release date: 2012-05-16, Last modification date: 2024-02-28)

Primary citation

Yu, W.,Chory, E.J.,Wernimont, A.K.,Tempel, W.,Scopton, A.,Federation, A.,Marineau, J.J.,Qi, J.,Barsyte-Lovejoy, D.,Yi, J.,Marcellus, R.,Iacob, R.E.,Engen, J.R.,Griffin, C.,Aman, A.,Wienholds, E.,Li, F.,Pineda, J.,Estiu, G.,Shatseva, T.,Hajian, T.,Al-Awar, R.,Dick, J.E.,Vedadi, M.,Brown, P.J.,Arrowsmith, C.H.,Bradner, J.E.,Schapira, M.
Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.
Nat Commun, 3:1288-1288, 2012

PubMed 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.

PubMed: 23250418
DOI: 10.1038/ncomms2304

Experimental method

X-RAY DIFFRACTION (2.4 Å)