3ubw | pdb_00003ubw
Complex of 14-3-3 isoform epsilon, a Mlf1 phosphopeptide and a small fragment hit from a FBDD screen
Structural highlights
Disease[1433E_HUMAN] Distal 17p13.3 microdeletion syndrome;17p13.3 microduplication syndrome;Miller-Dieker syndrome. [MLF1_HUMAN] A chromosomal aberration involving MLF1 is a cause of myelodysplastic syndrome (MDS). Translocation t(3;5)(q25.1;q34) with NPM1/NPM. Function[1433E_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. [MLF1_HUMAN] Involved in lineage commitment of primary hemopoietic progenitors by restricting erythroid formation and enhancing myeloid formation. Interferes with erythropoietin-induced erythroid terminal differentiation by preventing cells from exiting the cell cycle through suppression of CDKN1B/p27Kip1 levels. Suppresses RFWD2/COP1 activity via CSN3 which activates p53 and induces cell cycle arrest. Binds DNA and affects the expression of a number of genes so may function as a transcription factor in the nucleus.[1] Publication Abstract from PubMedMyeloid leukaemia factor 1 (MLF1) binds to 14-3-3 adapter proteins by a sequence surrounding Ser34 with the functional consequences of this interaction largely unknown. We present here the high-resolution crystal structure of this binding motif [MLF1(29-42)pSer34] in complex with 14-3-3epsilon and analyse the interaction with isothermal titration calorimetry. Fragment-based ligand discovery employing crystals of the binary 14-3-3epsilon/MLF1(29-42)pSer34 complex was used to identify a molecule that binds to the interface rim of the two proteins, potentially representing the starting point for the development of a small molecule that stabilizes the MLF1/14-3-3 protein-protein interaction. Such a compound might be used as a chemical biology tool to further analyse the 14-3-3/MLF1 interaction without the use of genetic methods. Database Structural data are available in the Protein Data Bank under the accession number(s) 3UAL [14-3-3epsilon/MLF1(29-42)pSer34 complex] and 3UBW [14-3-3epsilon/MLF1(29-42)pSer34/3-pyrrolidinol complex] Structured digital abstract * 14-3-3 epsilon and MLF1 bind by x-ray crystallography (View interaction) * 14-3-3 epsilon and MLF1 bind by isothermal titration calorimetry (View Interaction: 1, 2). Structural insights of the MLF1/14-3-3 interaction.,Molzan M, Weyand M, Rose R, Ottmann C FEBS J. 2011 Dec 8. doi: 10.1111/j.1742-4658.2011.08445.x. PMID:22151054[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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