3P8H

Crystal structure of L3MBTL1 (MBT repeat) in complex with a nicotinamide antagonist

3P8H の概要

• エントリーDOI: 10.2210/pdb3p8h/pdb
• 分子名称: Lethal(3)malignant brain tumor-like protein, 3-bromo-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridine, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: lethal(3) malignant brain tumor-like protein, l(3)mbt-like protein, structural genomics consortium, sgc, mbt repeat, transcriptional repression, methylated lysines on histone proteins, transcription
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : Q9Y468
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 112480.56

構造登録者

Lam, R.,Herold, J.M.,Ouyang, H.,Tempel, W.,Gao, C.,Ravichandran, M.,Senisterra, G.,Bountra, C.,Weigelt, J.,Arrowsmith, C.H.,Edwards, A.M.,Vedadi, M.,Kireev, D.,Frye, S.V.,Brown, P.J.,Structural Genomics Consortium (SGC) (登録日: 2010-10-13, 公開日: 2010-11-03, 最終更新日: 2023-09-06)

主引用文献

Herold, J.M.,Wigle, T.J.,Norris, J.L.,Lam, R.,Korboukh, V.K.,Gao, C.,Ingerman, L.A.,Kireev, D.B.,Senisterra, G.,Vedadi, M.,Tripathy, A.,Brown, P.J.,Arrowsmith, C.H.,Jin, J.,Janzen, W.P.,Frye, S.V.
Small-molecule ligands of methyl-lysine binding proteins.
J.Med.Chem., 54:2504-2511, 2011

PubMed Abstract: Proteins which bind methylated lysines ("readers" of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a repressed transcriptional state. Antagonists of MBT domains would serve as probes to interrogate the functional role of these proteins and initiate the chemical biology of methyl-lysine readers as a target class. Small-molecule MBT antagonists were designed based on the structure of histone peptide-MBT complexes and their interaction with MBT domains determined using a chemiluminescent assay and ITC. The ligands discovered antagonize native histone peptide binding, exhibiting 5-fold stronger binding affinity to L3MBTL1 than its preferred histone peptide. The first cocrystal structure of a small molecule bound to L3MBTL1 was determined and provides new insights into binding requirements for further ligand design.

PubMed: 21417280
DOI: 10.1021/jm200045v

実験手法

X-RAY DIFFRACTION (2.55 Å)