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Conformational cooperativity is a universal molecular effect mechanism and plays a critical role in signaling pathways. However, it remains a challenge to develop artificial molecular networks regulated by conformational cooperativity, due to the difficulties in programming and controlling multiple structural interactions. Herein, we develop a cooperative strategy by programming multiple conformational signals, rather than chemical signals, to regulate protein-oligonucleotide signal transduction, taking advantage of the programmability of allosteric DNA constructs. We generate a cooperative regulation mechanism, by which increasing the loop lengths at two different structural modules induced the opposite effects manifesting as down- and up-regulation. We implement allosteric logic operations by using two different proteins. Further, in cell culture we demonstrate the feasibility of this strategy to cooperatively regulate gene expression of PLK1 to inhibit tumor cell proliferation, responding to orthogonal protein-signal stimulation. This programmable conformational cooperativity paradigm has potential applications in the related fields.
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http://dx.doi.org/10.1038/s41467-023-40589-z | DOI Listing |
J Biomol Struct Dyn
September 2025
Enzyme and Microbial Technology Research Center, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
A thermostable paraoxonase (S3wahi-PON) from sp. strain S3wahi was recently characterised and shown to possess stability across a broad temperature range. This study expands upon the initial biochemical characterisation of S3wahi-PON by investigating the structural determinants and conformational adaptability that contribute to its thermostability, using an integrated approach that combines biophysical techniques and molecular dynamics (MD) simulations across a temperature range of 10 °C to 90 °C.
View Article and Find Full Text PDFAnal Chim Acta
November 2025
School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China; Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, Hefei, 230009, China; Intelligent Interconnected Systems Laboratory of A
Background: Copper is a vital trace element that plays a crucial role in various physiological processes due to its ability to exist in multiple oxidation states. Inspired by natural enzymes, researchers have developed copper-based nanozymes that mimic enzyme functions, offering cost-effective and stable alternatives to traditional enzymes. Despite their promising properties, the design and synthesis of these nanozymes can be complex and challenging.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
September 2025
CFisUC, Department of Physics, University of Coimbra, 3004-516, Coimbra, Portugal.
With the goal of manipulating (bio)chemical processes, photoswitches emerge as important assets in molecular nanotechnology. To guide synthetic strategies toward increasingly more efficient systems, conformational dynamics studies performed with atomic rigor are in demand, particularly if this information can be extracted with control over the size of a perturbing solvation layer. Here, we use jet-cooled rotational spectroscopy and quantum chemistry calculations to unravel the structure and micro-hydration dynamics of a prototype photoswitch.
View Article and Find Full Text PDFTargeted protein degradation (TPD) through the ubiquitin-proteasome system is driven by compound-mediated polyubiquitination of a protein-of-interest by an E3 ubiquitin (Ub) ligase. To date, relatively few E3s have been successfully utilized for TPD and the governing principles of functional ternary complex formation between the E3, degrader, and protein target remain elusive. FBXO22 has recently been harnessed by several groups to target different proteins for degradation.
View Article and Find Full Text PDFJ Mol Biol
September 2025
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:
The precise spatial and temporal regulation of gene expression through enhancer-promoter (E-P) interactions represents a fundamental mechanism underlying cellular differentiation and organismal development in multicellular eukaryotes. Despite extensive studies on enhancer-mediated gene regulation, a systematic understanding of how specific E-P configurations affect transcriptional dynamics remains incomplete. Recent advances in live-imaging, single-cell assays, and chromatin conformation capture technologies have enabled unprecedented insights into these dynamic regulatory processes by providing temporal resolution and single-cell specificity that complement traditional population-based approaches.
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