Structural Basis for Lower Lysine Methylation State-Specific Readout by MBT Repeats of L3MBTL1 and an Engineered PHD Finger

Haitao Li, Wolfgang Fischle, Wooikoon Wang, Elizabeth M. Duncan, Lena Liang, Satoko Murakami-Ishibe, C. David Allis, Dinshaw J. Patel

Research output: Contribution to journalArticlepeer-review

167 Scopus citations


Human L3MBTL1, which contains three malignant brain tumor (MBT) repeats, binds monomethylated and dimethylated lysines, but not trimethylated lysines, in several histone sequence contexts. In crystal structures of L3MBTL1 complexes, the monomethyl- and dimethyllysines insert into a narrow and deep cavity of aromatic residue-lined pocket 2, while a proline ring inserts into shallower pocket 1. We have also engineered a single Y to E substitution within the aromatic cage of the BPTF PHD finger, resulting in a reversal of binding preference from trimethyl- to dimethyllysine in an H3K4 sequence context. In both the "cavity insertion" (L3MBTL1) and "surface groove" (PHD finger) modes of methyllysine recognition, a carboxylate group both hydrogen bonds and ion pairs to the methylammonium proton. Our structural and binding studies of these two modules provide insights into the molecular principles governing the decoding of lysine methylation states, thereby highlighting a methylation state-specific layer of histone mark readout impacting on epigenetic regulation.

Original languageEnglish
Pages (from-to)677-691
Number of pages15
JournalMolecular Cell
Issue number4
StatePublished - Nov 30 2007

Bibliographical note

Funding Information:
D.J.P. is supported by funds from the Abby Rockefeller Mauze Trust and the Dewitt Wallace and Maloris Foundations, and C.D.A. is supported by an NIH MERIT award and funds from Rockefeller University. We thank Drs. Nagesh Kalakonda, Stephen D. Nimer, Alex Ruthenburg, Sean Taverna, Valentina Tereshko, and Joanna Wysocka for their helpful advice and comments. We thank the Peptide Core Facilities at Sloan-Kettering (S.S. Yi at Microchemistry and Proteomics) and Rockefeller University for the synthesis and purification of K4-methylated H3 peptides. We would like to thank the staff at beamline NE CAT 24ID-C of the Advanced Photon Source at the Argonne National Laboratory, supported by the US Department of Energy, for assistance with data collection.


  • DNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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