Conformationally defined enantiomeric local anesthetics and fluorescent dyes were synthesized. Neither the local anesthetics nor the fluorescent probes showed stereospecificity in interacting with nerve membranes. The fluorescence signals generated by the dyes showed excellent correlation with the time course and shape of the nerve action potential.
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Sci Adv
January 2025
Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA.
In single cells, variably sized nanoscale chromatin structures are observed, but it is unknown whether these form a cohesive framework that regulates RNA transcription. Here, we demonstrate that the human genome is an emergent, self-assembling, reinforcement learning system. Conformationally defined heterogeneous, nanoscopic packing domains form by the interplay of transcription, nucleosome remodeling, and loop extrusion.
View Article and Find Full Text PDFJ Am Chem Soc
January 2025
Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States.
Chemical selectivity is traditionally understood in the context of rigid molecular scaffolds with precisely defined local coordination and chemical environments that ultimately facilitate a given transformation of interest. By contrast, nature leverages dynamic structures and strong coupling to enable specific interactions with target species in otherwise complex media. Taking inspiration from nature, we demonstrate unconventional selectivity in the solvent extraction of light over heavy lanthanides using a conformationally flexible ligand called octadecyl acyclopa (ODA).
View Article and Find Full Text PDFJ Org Chem
January 2025
Department of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Isoprenylation of the indole C3-position of tryptophan accompanied by cyclization (c-Trp) is one of the most attractive post-translational modifications because of C-C bond formation and drastic conformational alteration. As the modification generates two stereoisomers of the 6/5/5-fused ring system and consequently, a mixture of four possible conformations as considered in proline, it is expected to influence the biological activity in quorum sensing pheromone ComX containing the c-Trp residue. In this study, the simultaneous control of the amide equilibrium and pyrrolidine ring puckering was achieved by utilizing an N-carbamoylated and α-methylated 6/5/5-fused ring system.
View Article and Find Full Text PDFNature
December 2024
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA.
Non-ribosomal peptide synthetases are assembly line biosynthetic pathways that are used to produce critical therapeutic drugs and are typically arranged as large multi-domain proteins called megasynthetases. They synthesize polypeptides using peptidyl carrier proteins that shuttle each amino acid through modular loading, modification and elongation steps, and remain challenging to structurally characterize, owing in part to the inherent dynamics of their multi-domain and multi-modular architectures. Here we have developed site-selective crosslinking probes to conformationally constrain and resolve the interactions between carrier proteins and their partner enzymatic domains.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
November 2024
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA.
Collagens are the foundational component of diverse tissues, including skin, bone, cartilage, and basement membranes, and are the most abundant protein class in animals. The fibrillar collagens are large, complex, multidomain proteins, all containing the characteristic triple helix motif. The most prevalent collagens are heterotrimeric, meaning that cells express at least two distinctive procollagen polypeptides that must assemble into specific heterotrimer compositions.
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