3P8H
Crystal structure of L3MBTL1 (MBT repeat) in complex with a nicotinamide antagonist
Summary for 3P8H
| Entry DOI | 10.2210/pdb3p8h/pdb |
| Descriptor | Lethal(3)malignant brain tumor-like protein, 3-bromo-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridine, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | 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 |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus : Q9Y468 |
| Total number of polymer chains | 3 |
| Total formula weight | 112480.56 |
| Authors | 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) (deposition date: 2010-10-13, release date: 2010-11-03, Last modification date: 2023-09-06) |
| Primary citation | 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 Cited by 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: 21417280DOI: 10.1021/jm200045v PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.55 Å) |
Structure validation
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