A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity
Chava Kimchi-Sarfaty,Jung Mi Oh,In-Wha Kim,Zuben E. Sauna,Anna Maria Calcagno,Suresh V. Ambudkar,Michael M. Gottesman +6 more
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TLDR
It is hypothesized that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.Abstract:
Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the Multidrug Resistance 1 (MDR1) gene, part of a haplotype previously linked to altered function of the MDR1 gene product P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA and protein levels, but altered conformations, were found for wild-type and polymorphic P-gp. We hypothesize that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.read more
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疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A
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Coding-sequence determinants of gene expression in Escherichia coli.
TL;DR: In this analysis, mRNA folding and associated rates of translation initiation play a predominant role in shaping expression levels of individual genes, whereas codon bias influences global translation efficiency and cellular fitness.
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mRNA-based therapeutics — developing a new class of drugs
TL;DR: This Review provides a comprehensive overview of the current state of mRNA-based drug technologies and their applications, and discusses the key challenges and opportunities in developing these into a new class of drugs.
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Synonymous but not the same: the causes and consequences of codon bias.
Joshua B. Plotkin,Grzegorz Kudla +1 more
TL;DR: Ongoing work to quantify the dynamics of initiation and elongation is as important for understanding natural synonymous variation as it is for designing transgenes in applied contexts.
References
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疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Journal ArticleDOI
Multidrug resistance in cancer: role of ATP–dependent transporters
TL;DR: The ability to predict and circumvent drug resistance is likely to improve chemotherapy, and it has become apparent that resistance exists against every effective drug, even the authors' newest agents.
Journal ArticleDOI
The codon Adaptation Index--a measure of directional synonymous codon usage bias, and its potential applications.
Paul M. Sharp,Wen-Hsiung Li +1 more
TL;DR: A simple, effective measure of synonymous codon usage bias, the Codon Adaptation Index, is detailed, useful for predicting the level of expression of a gene, for assessing the adaptation of viral genes to their hosts, and for making comparisons ofCodon usage in different organisms.
Journal ArticleDOI
Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo
Sven Hoffmeyer,Oliver Burk,O. von Richter,H. P. Arnold,Jürgen Brockmöller,Andreas Johne,Ingolf Cascorbi,Thomas Gerloff,Ivar Roots,Eichelbaum Michel,Ulrich Brinkmann +10 more
TL;DR: A significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function is observed and this polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of M DR-1.
Journal ArticleDOI
Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues.
TL;DR: Pgp expression in capillaries of the brain and testis may explain the failure of drugs such as vincristine and actinomycin-D to penetrate into tissues, allowing them to remain as pharmacological sanctuaries for malignant cells.
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