Hot spots are located by virtual alanine-scanning consensus predictions over three different energy functions and two different single-structure representations of the complex. Using the MP1-p14 scaffolding complex from the mitogen-activated protein kinase signaling pathway as model system, we explored a structure-based computational protocol to probe and characterize binding affinity hot spots at protein-protein interfaces. Our study provides the first proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1 protein–protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins. MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. Determination of co-crystal structures of two potent peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K i < 1 nM and function as potent antagonists of MLL1 activity in more » a fully reconstituted in vitro H3K4 methyltransferase assay. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH–, the minimum binding motif derived from MLL1. The MLL1/WDR5 protein–protein interaction is essential for MLL1 enzymatic activity. Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The scientists suggest it may be possible to generalize that this action could describe the role of scaffold proteins in other signaling pathways.= , This suggests that Shc1 acts as a temporal switch, which, by separating interaction pathways in time, directs the signaling output of RTK activation to either survival pathways, or cell migration pathways. The proteins involved in signaling that promotes cell division were bound early in the process, while those involved in cytoskeletal rearrangement were bound later. They then analyzed which proteins were bound to Shc1 at different stages following activation of RTK. The researchers first mapped all possible interactions between Shc1 and other cellular proteins and found 23 new Shc1-interacting proteins involved in various cellular processes. Transduction of the signal culminates in altered gene expression, which leads to an array of potential cell fates. Upon activation, RTK recruits and phosphorylates the intracellular scaffold protein Shc1, which in turn binds downstream signaling proteins. The researchers, including Mohamed Soliman of Cairo University, considered the function of Receptor Tyrosine Kinase (RTK) to try to understand why it is a necessary mediator in this process. Both spatial and temporal precision of these signaling cascades are integral to elicit the required cellular response.Ī study published in Nature last week outlined attempts by scientists to understand the role of scaffold protein in cell signaling. Intricate, exquisitely coordinated networks of cell-surface and intracellular proteins work together to relay signals received from outside the cell to the nucleus, regulating cell fate and activity. Building an understanding of scaffold protein in cell signaling
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