6ghp
14-3-3sigma in complex with a TASK3 peptide stabilized by semi-synthetic natural product FC-NAc
Structural highlights
Disease[KCNK9_HUMAN] Intellectual deficit, Birk-Barel type. Birk-Barel mental retardation dysmorphism syndrome (BIBAS) [MIM:612292]: A syndrome characterized by mental retardation, hypotonia, hyperactivity, and facial dysmorphism. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] Function[1433S_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. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. [KCNK9_HUMAN] pH-dependent, voltage-insensitive, background potassium channel protein.[2] [3] Publication Abstract from PubMedThe natural product family of fusicoccanes are stabilizers of 14-3-3 mediated protein-protein interactions (PPIs), some of which possess antitumor activity. In this study, we present the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency. Synthesis of a focused library, followed by characterization by fluorescence polarization, mutational studies and X-ray crystallography confirmed the power of the MD-based design approach, revealing the potential for an additional hydrogen bond with the 14-3-3 protein which significantly increased potency. Additionally, these compounds exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small molecule PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compounds, as well as allowing the study of the fundamental principles behind PPI stabilization. Rationally Designed Semi-Synthetic Natural Product Analogues for Stabilization of 14-3-3 Protein-Protein Interactions.,Ottmann C, Andrei SA, de Vink P, Sijbesma E, Han L, Brunsveld L, Kato N, Higuchi Y Angew Chem Int Ed Engl. 2018 Jul 19. doi: 10.1002/anie.201806584. PMID:30025189[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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