5KJN

SMYD2 in complex with AZ506

Summary for 5KJN

• Entry DOI: 10.2210/pdb5kjn/pdb
• Related: 5KJK 5KJL 5KJM
• Descriptor: N-lysine methyltransferase SMYD2, S-ADENOSYLMETHIONINE, (R,R)-2,3-BUTANEDIOL, ... (7 entities in total)
• Functional Keywords: tranferase, histone methyltransferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol : Q9NRG4
• Total number of polymer chains: 1
• Total formula weight: 51061.66

Authors

Ferguson, A. (deposition date: 2016-06-20, release date: 2016-12-07, Last modification date: 2023-09-27)

Primary citation

Cowen, S.D.,Russell, D.,Dakin, L.A.,Chen, H.,Larsen, N.A.,Godin, R.,Throner, S.,Zheng, X.,Molina, A.,Wu, J.,Cheung, T.,Howard, T.,Garcia-Arenas, R.,Keen, N.,Pendleton, C.S.,Pietenpol, J.A.,Ferguson, A.D.
Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors.
J. Med. Chem., 59:11079-11097, 2016

PubMed Abstract: Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes.

PubMed: 28002961

Experimental method

X-RAY DIFFRACTION (2.72 Å)