Complex Motivic Analysis

Chapter 7 establishes the rules and guidelines for complex motivic analysis (CMA). CMA is the more advanced mode of motivic analysis, which centers around the activity of a larger, network-type motive composed of elements from many domains (similar to Schoenberg’s Grundgestalt). The chapter first provides an introduction to the expanded format for motive, including guidance on which domains to include and the proper format for each. It then guides readers through construction of a complex motive for a short Brahms waltz. The remainder of the chapter is given over to describing the paired end products of CMA, which are (1) an Organic Map illustrating the most significant motivic connections in the manner of an enhanced BMA, and (2) a “Narrative” that tallies and charts the number of Complex elements exhibited by each surface segment of the work. The result of the latter process is a Narrative Curve that charts the work’s fluctuating level of organicism and directly reflects the piece’s CMA archetype. The chapter concludes with demonstration of a full CMA analysis of the Brahms waltz.

Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ

The peroxisome proliferator-activated receptor (PPAR) family comprises three subtypes: PPARα, PPARγ, and PPARδ. PPARδ transcriptionally modulates lipid metabolism and the control of energy homeostasis; therefore, PPARδ agonists are promising agents for treating a variety of metabolic disorders. In the present study, we develop a panel of rationally designed PPARδ agonists. The modular motif affords efficient syntheses using building blocks optimized for interactions with subtype-specific residues in the PPARδ ligand-binding domain (LBD). A combination of atomic-resolution protein X-ray crystallographic structures, ligand-dependent LBD stabilization assays, and cell-based transactivation measurements delineate structure–activity relationships (SARs) for PPARδ-selective targeting and structural modulation. We identify key ligand-induced conformational transitions of a conserved tryptophan side chain in the LBD that trigger reorganization of the H2′–H3 surface segment of PPARδ. The subtype-specific conservation of H2′–H3 sequences suggests that this architectural remodeling constitutes a previously unrecognized conformational switch accompanying ligand-dependent PPARδ transcriptional regulation.

Evolutionary, Structural and Biochemical Evidence for a New Interaction Site of the Leptin Obesity Protein

The Leptin protein is central to the regulation of energy metabolism in mammals. By integrating evolutionary, structural, and biochemical information, a surface segment, outside of its known receptor contacts, is predicted as a second interaction site that may help to further define its roles in energy balance and its functional differences between humans and other mammals.