P-glycoprotein (P-gp) is well known for multidrug resistance in drug therapy. Its over-expression results into the increased efflux of therapeutic agents rendering them inefficacious. A clear understanding of P-gp efflux mechanism and substrate/inhibitor interactions during the course of efflux cycle will be crucial for designing effective P-gp inhibitors, and therapeutic agents that are non-substrate to P-gp. In the present work, we have modeled P-gp in three different catalytic states. These models were utilized for elucidation of P-gp translocation mechanism using multi-targeted molecular dynamics (MTMD). The gradual changes occurring in P-gp structure from inward open to outward open conformation were sampled out. A detailed investigation of conformational changes occurring in trans-membrane domains (TMDs) during the course of catalytic cycle was carried out. Movements of each TM helices in response to pronounced twisting and translatory motion of NBDs were measured quantitatively. The role of intracellular coupling helices (ICHs) during the structural transition of P-gp was studied, and observed as vital links for structural transition. A close observation of displacements and conformational changes in the residues lining drug-binding pocket was also carried out. Further, we have analyzed the molecular interactions of P-gp substrates/inhibitors during the P-gp translocation to find out how stable binding interactions of a compound at drug-binding site(s) in open conformation, becomes highly destabilized in closed conformation. The study revealed striking differences between the molecular interactions of substrate and inhibitor; inhibitors showed a tendency to maintain stable binding interactions during the catalytic transition cycle.
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http://dx.doi.org/10.1016/j.bbamem.2014.07.018 | DOI Listing |
J Colloid Interface Sci
January 2025
College of Light Industry and Food Engineering, Nanjing Forestry University, Jiangsu Co-Innovation Center for Efficient Processing and Utilization of Forest Resources, Nanjing 210037 China. Electronic address:
Surface-enhanced Raman scattering (SERS) is a highly sensitive technology to detect target analytes. The construction of dynamic "hot-spots" represents a significant approach to enhancing detection sensitivity. Herein, a hybrid plasma platform with dynamic "hot-spots" was developed for SERS recognition based on the assembly of gold nanospheres (AuNSs) on temperature-sensitive bacterial cellulose (BC) film grafted with poly(N-isopropylacrylamide) (PNIPAM).
View Article and Find Full Text PDFPharmacol Ther
January 2025
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects.
View Article and Find Full Text PDFStructure
January 2025
Department of Chemistry, Emory University, Atlanta, GA 30322, USA. Electronic address:
Thio/selenoimidazole Nπ-methyltransferases are an emerging family of enzymes catalyzing the final step in the production of the S/Se-containing histidine-derived antioxidants ovothiol and ovoselenol. These enzymes, prevalent in prokaryotes, show minimal sequence similarity to other methyltransferases, and the structural determinants of their reactivities remain poorly understood. Herein, we report ligand-bound crystal structures of OvsM from the ovoselenol pathway as well as a member of a previously unknown clade of standalone ovothiol-biosynthetic Nπ-methyltransferases, which we have designated OvoM.
View Article and Find Full Text PDFFood Chem
January 2025
College of Food and Bioengineering, Xihua University, Chengdu 610039, China; Chongqing Key Laboratory of Speciality Food Co-Built by Sichuan and Chongqing, Chengdu 610039, China; School of Future Food Modern Industry, Xihua University, Chengdu 610039, China. Electronic address:
The effects of high-intensity ultrasound (HIU) on the dispersibility of myofibrillar proteins (MPs) in low-salt medium were investigated. HIU-assisted STPP or TSPP could sharply improve the solubility and dispersibility of MPs (from 38.12 % to 94.
View Article and Find Full Text PDFJ Inorg Biochem
January 2025
Department of Chemistry, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address:
Due to its commercial availability and well-defined structure, the interaction between bovine protein β-lactoglobulin (βLG) and a wide variety of non-native ligands - including transition metal complexes - has been explored, but its application as an artificial metalloenzyme scaffold is limited. This protein is hypothesized to transport fatty acids and other nutrients during juvenile development, and it binds hydrophobic ligands inside a binding pocket constructed upon an 8-stranded β-barrel, called the 'calyx'. Herein, we compare the binding behavior of two rhenium(anthracene-bispyridine) ('Anth-py') tricarbonyl complexes, one with a 12‑carbon chain appended to the ligand scaffold ('Anth-py') to βLG.
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