Buried polar residues averaged under 30% relative SASA (Supporting Information, Figure S6)

Buried polar residues averaged under 30% relative SASA (Supporting Information, Figure S6). extensive analysis of coiled coil motifs, the interactions between pre-formed coiled coils and globular proteins have not been systematically analyzed. This article identifies crucial features of these helical interfaces with respect to coiled coil TLR7-agonist-1 and other helical PPIs. We expect the analysis to prove useful for the rational design of modulators of this fundamental class of protein assemblies. Introduction Mimicry of interfacial protein segments has led to new classes of rationally designed inhibitors of proteinCprotein interactions (PPIs).1?8 The identification and analysis of protein complexes mediated by protein secondary structures provide a platform for these explorations.3,4,9 We have recently examined the full set of protein complexes in the Protein Data Lender mediated by -helices10?13 and -strands.14 Our work, along with efforts by Kritzer et al.15 to define loop motifs at protein interfaces, aims both to the interactions present in the Protein Data Lender and to effective starting points for the TLR7-agonist-1 design of PPI inhibitors.4,9 Individual secondary structures are critical elements of protein interfaces; however, many PPIs feature more complex modes of binding, suggesting a potential role for synthetic tertiary structure mimetics16,17 or miniproteins18,19 Rabbit polyclonal to IL11RA as attractive candidates for the design of new classes of PPI inhibitors. Miniproteins consisting of helical bundles, -sheet barrels, and loops, along with synthetic antibodies,20?22 are now routinely used to enrich ligands for protein targets, especially for extracellular receptors. In an effort to expand our atomic analysis of protein structural data beyond interactions that can be mediated by a single secondary structure element alone, we have developed new methodology to create a database of helical dimers at proteinCprotein interfaces (DippDB). We chose to begin our survey of protein tertiary interactions by focusing on helix dimers because the dimer is the simplest all-helical tertiary structure stoichiometry. Coiled coils and helical bundles are well comprehended and have been extensively studied in diverse biochemical and biophysical contexts.23?27 Dimeric coiled coils or similarly structured motifs such as bundles play essential functions in mediating biological processes, iconically driving the multimerization and stabilization of proteins involved in transcription TLR7-agonist-1 factor complexes and vesicular trafficking, among other critical functions.25,28 Several computational approaches have been implemented to predict coiled coil-mediated interactions by their pairwise and multimeric residue correlations.29?32 Seminal studies have produced a comprehensive dataset of the coiled coil interactome.33?35 However, computational and experimental methods for the analysis of coiled coils described thus far are largely devoted to characterization of forces that coiled coil formation. To complement these studies, we sought to analyze interactions of helical dimers with globular proteins as a step toward the rational design of coiled coil mimetics as PPI inhibitors.16,17 Though canonical TLR7-agonist-1 coiled coils possess supercoiling and particular packing TLR7-agonist-1 properties, we did not impose these requirements, stipulating only that this helices be proximal and well-oriented. Since our motivation for developing this dataset is usually to identify interactions that may not be inhibited by secondary structure mimics, we also required that crucial binding residues be located on helices. These criteria retain structures of high structural similarity to a coiled coil but eliminate canonical all-alpha tertiary structure motifs like the helix-loop-helix and helix-turn-helix DNA binding domains, whose interhelical angles are far from parallel or antiparallel. Examination of the helix dimer dataset suggests that coiled coil interfaces can be divided into three broad categories (Physique ?Physique11) according to their conversation stoichiometry. Case 1 features a helical dimer from one protein interacting with a single partner protein. In Case 2, a helical dimer from one protein interacts with two different protein partners. In Case 3, a single helical dimer motif at the interface between partner proteins. We anticipate that helical dimers in Case 3 would favor different interacting residues from examples in Cases 1 and 2, because in.

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