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Discovery of a Chemical Probe for the L3MBTL3 Methyllysine Reader Domain

Discovery of a Chemical Probe for the L3MBTL3 Methyllysine Reader Domain

Lindsey I James, Dalia Barsyte-Lovejoy, Nan Zhong, Liubov Krichevsky, Victoria K Korboukh, J Martin Herold, Christopher J MacNevin, Jacqueline L Norris, Cari A Sagum, Wolfram Tempel, Edyta Marcon, Hongbo Guo, etc.

Nat Chem Biol. 2013 Mar;9(3):184-91.

PMID: 23292653

Abstract:

We describe the discovery of UNC1215, a potent and selective chemical probe for the methyllysine (Kme) reading function of L3MBTL3, a member of the malignant brain tumor (MBT) family of chromatin-interacting transcriptional repressors. UNC1215 binds L3MBTL3 with a K(d) of 120 nM, competitively displacing mono- or dimethyllysine-containing peptides, and is greater than 50-fold more potent toward L3MBTL3 than other members of the MBT family while also demonstrating selectivity against more than 200 other reader domains examined. X-ray crystallography identified a unique 2:2 polyvalent mode of interaction between UNC1215 and L3MBTL3. In cells, UNC1215 is nontoxic and directly binds L3MBTL3 via the Kme-binding pocket of the MBT domains. UNC1215 increases the cellular mobility of GFP-L3MBTL3 fusion proteins, and point mutants that disrupt the Kme-binding function of GFP-L3MBTL3 phenocopy the effects of UNC1215 on localization. Finally, UNC1215 was used to reveal a new Kme-dependent interaction of L3MBTL3 with BCLAF1, a protein implicated in DNA damage repair and apoptosis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1415800439	UNC1215		1415800-43-9	Price

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