In ion channels, 'rings' of ionized side chains that decorate the walls of the permeation pathway often lower the energetic barrier to ion conduction. Using single-channel electrophysiological recordings, we studied the poorly understood ring of four glutamates (and one glutamine) that dominates this catalytic effect in the muscle nicotinic acetylcholine receptor ('the intermediate ring of charge'). We show that all four wild-type glutamate side chains are deprotonated in the range of 6.0-9.0 pH, that only two of them contribute to the size of the single-channel current, that these side chains must be able to adopt alternate conformations that either allow or prevent their negative charges from increasing the rate of cation conduction and that the location of these glutamate side chains squarely at one of the ends of the transmembrane pore is critical for their largely unshifted pK(a) values and for the unanticipated impact of their conformational flexibility on cation permeation.
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http://dx.doi.org/10.1038/nchembio.1092 | DOI Listing |
Biotechnol Adv
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TEDA Institute of Biological Sciences and Biotechnology, Tianjin Key Laboratory of Microbial Functional Genomics, Nankai University, Tianjin, PR China; Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin, PR China; Nankai International Advanced Research Institute, Nankai University, Shenzhen, China. Electronic address:
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Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.
Cancer manifests as uncontrolled cell proliferation. Tankyrase, a poly(ADP-ribose) polymerase member, is vital in Wnt signal transmission, making it a promising cancer therapy target. The Wnt/β-catenin pathway regulates critical biological processes like genomic stability, gene expression, energy utilization, and apoptosis.
View Article and Find Full Text PDFJ Org Chem
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Laboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotechnology, Heisenbergstrasse 11, 48149 Münster, Germany.
Xanthine nucleosides play a significant role in the expansion of the four-letter genetic code. Herein, 7-functionalized 8-aza-7-deazaxanthine ribo- and 2'-deoxyribonucleosides are described. 2-Amino-6-alkoxy nucleosides were converted to halogenated 8-aza-7-deazaxanthine nucleosides by deamination followed by hydroxy/alkoxy substitution.
View Article and Find Full Text PDFJ Med Chem
January 2025
Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong SAR 999077, China.
CDK4/6 inhibitors are effective in treating HR/HER2 breast cancer but face limitations due to therapeutic resistance and hematological toxicity, particularly from strong CDK6 inhibition. To address these challenges, designing selective inhibitors targeting specific cyclin-dependent kinases (CDK) members could offer clinical advantages and broaden CDK inhibitor indications. However, the highly conserved binding pockets of CDKs complicate selective targeting.
View Article and Find Full Text PDFProteins
January 2025
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India.
Short-length peptides are used as therapeutics due to their high target specificity and low toxicity; for example, peptides are designed for targeting the interaction between oncogenic protein p53 and E3 ubiquitin ligase MDM2. These peptide therapeutics form a class of successful inhibitors. To design such peptide-based inhibitors, stapling is one of the methods in which amino acid side chains are stitched together to get conformationally rigid peptides, ensuring effective binding to their partners.
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