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The design of enzymes with complex active sites that mediate multistep reactions remains an outstanding challenge. With serine hydrolases as a model system, we combined the generative capabilities of RFdiffusion with an ensemble generation method for assessing active site preorganization to design enzymes starting from minimal active site descriptions. Experimental characterization revealed catalytic efficiencies (/) up to 2.2x10 M s and crystal structures that closely match the design models (Cα RMSDs < 1 Å). Selection for structural compatibility across the reaction coordinate enabled identification of new catalysts in low-throughput screens with five different folds distinct from those of natural serine hydrolases. Our de novo approach provides insight into the geometric basis of catalysis and a roadmap for designing enzymes that catalyze multistep transformations.
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http://dx.doi.org/10.1126/science.adu2454 | DOI Listing |
Background: The unfolded protein response (UPR) enables myeloma cells to overcome the stress conditions arising from excessive proteosynthesis and thus provides a survival advantage for myeloma cells. Extramedullary disease is a more aggressive form of multiple myeloma in which myeloma cells lose their dependence on the bone marrow microenvironment and are able to infiltrate other tissues and organs. The pathogenesis of extramedullary disease is not fully elucidated yet.
View Article and Find Full Text PDFChembiochem
March 2025
University of Zurich: Universitat Zurich, Department of Chemistry, SWITZERLAND.
Quorum sensing allows bacteria to coordinate community-wide behaviours such as biofilm formation, virulence, and symbiosis. The diazeniumdiolate valdiazen has been identified in the opportunistic pathogen Burkholderia cenocepacia H111 as a novel quorum-sensing signal, yet its protein interactome has remained unexplored. In this study, we employed a chemoproteomic pulldown approach to identify potential valdiazen-binding proteins.
View Article and Find Full Text PDFJ Neuroinflammation
March 2025
Department of Neurology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315040, China.
Background: Disease-modifying therapies (DMTs) that prevent immune cell infiltration into the brain have demonstrated efficacy in multiple sclerosis (MS) treatment. However, their unpredictable adverse effects necessitate the development of safer therapeutic alternatives. The choroid plexus (ChP) functions as a crucial barrier against immune cell invasion, and previous studies have shown that preventing immune cell infiltration across the ChP reduces brain lesion in MS animal models.
View Article and Find Full Text PDFCommun Biol
March 2025
Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA.
Ixodes scapularis ticks transmit several medically important pathogens including Anaplasma phagocytophilum to humans and animals. In this study, we provide evidence that A. phagocytophilum modulates autophagy molecules for its survival in tick cells.
View Article and Find Full Text PDFInt J Mol Sci
March 2025
Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
The liver is the most lethal metastatic site in castration-resistant prostate cancer (CRPC). Overexpression of MET protein has been reported in CRPC, and is an important driver gene in androgen-independent CRPC cells. Mouse CRPC cell line CRTC2 was established by subcutaneous injection of hormone-sensitive PC cells (TRAMP-C2) in castrated nude mice.
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