5m36

The molecular tweezer CLR01 stabilizes a disordered protein-protein interface

spinqualitylabelsall models 5m36, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5m36 is a 4 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 5jiv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.45Å Ligands: 9SZ, BEZ, CSO, GOL, SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 1433Z_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. Publication Abstract from PubMed Protein regions that are involved in protein-protein interactions (PPIs) very often display a high degree of intrinsic disorder, which is reduced during the recognition process. A prime example is binding of the rigid 14-3-3 adapter proteins to their numerous partner proteins, whose recognition motifs undergo an extensive disorder-to-order transition. In this context, it is highly desirable to control this entropy-costly process using tailored stabilizing agents. This study reveals how the molecular tweezer CLR01 tunes the 14-3-3/Cdc25CpS216 protein-protein interaction. Protein crystallography, biophysical affinity determination and biomolecular simulations unanimously deliver a remarkable finding: a supramolecular "Janus" ligand can bind simultaneously to a flexible peptidic PPI recognition motif and to a well-structured adapter protein. This binding fills a gap in the protein-protein interface, "freezes" one of the conformational states of the intrinsically disordered Cdc25C protein partner and enhances the apparent affinity of the interaction. This is the first structural and functional proof of a supramolecular ligand targeting a PPI interface and stabilizing the binding of an intrinsically disordered recognition motif to a rigid partner protein. The Molecular Tweezer CLR01 Stabilizes a Disordered Protein-Protein Interface.,Bier D, Mittal S, Bravo-Rodriguez K, Sowislok A, Guillory X, Briels J, Heid C, Bartel M, Wettig B, Brunsveld L, Sanchez-Garcia E, Schrader T, Ottmann C J Am Chem Soc. 2017 Nov 2. doi: 10.1021/jacs.7b07939. PMID:29039919 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also 14-3-3 protein 3D structures

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