Exploring the ability of cyclic peptides to target SAM domains: a computational and experimental study(88 visite) Mercurio FA, Di Natale C, Pirone L, Vincenzi M, Marasco D, De Luca S, Pedone EM, Leone M
Impact factor: 2.641, Impact factor a 5 anni: 3.684
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Parole chiave: Epha2, Nmr, Sam Domains, Cyclic Peptides, Virtual Screening, Nmr Spectroscopy
, Helical Structures
, Protein-Protein Interactions
*** IBB - CNR *** ITALY., Consiglio Nazionale delle Ricerche, Istitute of Biostructures and Bioimaging, Via Mezzocannone 16, 80134, Naples, ITALY., Institute of Biostructures and Bioimaging, National Research Council, Via Mezzocannone 16, 80134, Naples, Italy. Department of Pharmacy, University of Naples "Federico II", Via Mezzocannone 16, 80134, Naples, Italy.
Sterile alpha motif (SAM) domains are protein interaction modules with a helical fold. SAM-SAM interactions often adopt the mid-loop (ML)/end-helix (EH) model, in which the C-terminal helix and adjacent loops of one SAM unit (EH site) bind the central regions of another SAM domain (ML site). Herein, an original strategy to attack SAM-SAM associations is reported. It relies on the design of cyclic peptides that target a region of the SAM domain positioned at the bottom side of the EH interface, which is thought to be important for the formation of a SAM-SAM complex. This strategy has been preliminarily tested by using a model system of heterotypic SAM-SAM interactions involving the erythropoietin-producing hepatoma kinase A2 (EphA2) receptor and implementing a multidisciplinary plan made up of computational docking studies, experimental interaction assays (by NMR spectroscopy and surface plasmon resonance techniques) and conformational analysis (by NMR spectroscopy and circular dichroism). This work further highlights how only a specific balance between flexibility and rigidity may be needed to generate modulators of SAM-SAM interactions.