4FL6

Crystal structure of the complex of the 3-MBT repeat domain of L3MBTL3 and UNC1215

Summary for 4FL6

• Entry DOI: 10.2210/pdb4fl6/pdb
• Descriptor: Lethal(3)malignant brain tumor-like protein 3, [2-(phenylamino)benzene-1,4-diyl]bis{[4-(pyrrolidin-1-yl)piperidin-1-yl]methanone}, UNKNOWN ATOM OR ION (3 entities in total)
• Functional Keywords: structural genomics consortium, sgc, chromatin modification, transcription repression, mbt repeat, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : Q96JM7
• Total number of polymer chains: 2
• Total formula weight: 78080.90

Authors

Zhong, N.,Tempel, W.,Ravichandran, M.,Dong, A.,Ingerman, L.A.,Graslund, S.,Frye, S.V.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Structural Genomics Consortium (SGC) (deposition date: 2012-06-14, release date: 2012-06-27, Last modification date: 2023-09-13)

Primary citation

James, L.I.,Barsyte-Lovejoy, D.,Zhong, N.,Krichevsky, L.,Korboukh, V.K.,Herold, J.M.,MacNevin, C.J.,Norris, J.L.,Sagum, C.A.,Tempel, W.,Marcon, E.,Guo, H.,Gao, C.,Huang, X.P.,Duan, S.,Emili, A.,Greenblatt, J.F.,Kireev, D.B.,Jin, J.,Janzen, W.P.,Brown, P.J.,Bedford, M.T.,Arrowsmith, C.H.,Frye, S.V.
Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain.
Nat. Chem. Biol., 9:184-191, 2013

PubMed 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.

PubMed: 23292653
DOI: 10.1038/nchembio.1157

Experimental method

X-RAY DIFFRACTION (2.55 Å)