Phosphoinositide Recognition Sites Are Blocked by Metabolite Attachment

Membrane readers take part in trafficking and signaling processes by localizing proteins to organelle surfaces and transducing molecular information. They accomplish this by engaging phosphoinositides (PIs), a class of lipid molecules which are found in different proportions in various cellular membranes. The prototypes are the PX domains, which exhibit a range of specificities for PIs. Our meta-analysis indicates that recognition of membranes by PX domains is specifically controlled by modification of lysine and arginine residues including acetylation, hydroxyisobutyrylation, glycation, malonylation, methylation and succinylation of sidechains that normally bind headgroups of phospholipids including organelle-specific PI signals. Such metabolite-modulated residues in lipid binding elements are named MET-stops here to highlight their roles as erasers of membrane reader functions. These modifications are concentrated in the membrane binding sites of half of all 49 PX domains in the human proteome and correlate with phosphoregulatory sites, as mapped using the Membrane Optimal Docking Area (MODA) algorithm. As these motifs are mutated and modified in various cancers and the responsible enzymes serve as potential drug targets, the discovery of MET-stops as a widespread inhibitory mechanism may aid in the development of diagnostics and therapeutics aimed at the readers, writers and erasers of the PI code.

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Abstract POSTER-TECH-1118: Meta-analysis of cancer microarray data sets reveals a germ line expression profile in ovarian cancers: new biomarkers and potential drug targets

10.1158/1557-3265.ovcasymp14-poster-tech-1118 ◽

2015 ◽

Author(s):

Ramsay McFarlane

Keyword(s):

Expression Profile ◽

Microarray Data ◽

Drug Targets ◽

Germ Line ◽

Meta Analysis ◽

Data Sets ◽

Potential Drug ◽

Ovarian Cancers ◽

New Biomarkers ◽

Potential Drug Targets

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Meta-Analysis of Polymyositis and Dermatomyositis Microarray Data Reveals Novel Genetic Biomarkers

Genes ◽

10.3390/genes10110864 ◽

2019 ◽

Vol 10 (11) ◽

pp. 864 ◽

Cited By ~ 2

Author(s):

Jaeseung Song ◽

Daeun Kim ◽

Juyeon Hong ◽

Go Woon Kim ◽

Junghyun Jung ◽

...

Keyword(s):

Drug Targets ◽

Meta Analysis ◽

Control Group ◽

Nucleotide Polymorphisms ◽

Immune Disorder ◽

Single Nucleotide ◽

Unfolded Protein ◽

Healthy Control ◽

Protein Response ◽

Potential Drug Targets

Polymyositis (PM) and dermatomyositis (DM) are both classified as idiopathic inflammatory myopathies. They share a few common characteristics such as inflammation and muscle weakness. Previous studies have indicated that these diseases present aspects of an auto-immune disorder; however, their exact pathogenesis is still unclear. In this study, three gene expression datasets (PM: 7, DM: 50, Control: 13) available in public databases were used to conduct meta-analysis. We then conducted expression quantitative trait loci analysis to detect the variant sites that may contribute to the pathogenesis of PM and DM. Six-hundred differentially expressed genes were identified in the meta-analysis (false discovery rate (FDR) < 0.01), among which 317 genes were up-regulated and 283 were down-regulated in the disease group compared with those in the healthy control group. The up-regulated genes were significantly enriched in interferon-signaling pathways in protein secretion, and/or in unfolded-protein response. We detected 10 single nucleotide polymorphisms (SNPs) which could potentially play key roles in driving the PM and DM. Along with previously reported genes, we identified 4 novel genes and 10 SNP-variant regions which could be used as candidates for potential drug targets or biomarkers for PM and DM.

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Pharmacologic treatment of negative symptoms

Managing Negative Symptoms of Schizophrenia ◽

10.1093/med/9780198840121.003.0005 ◽

2020 ◽

pp. 67-86

Author(s):

Pál Czobor ◽

István Bitter

Keyword(s):

Drug Targets ◽

Negative Symptoms ◽

First Generation ◽

Meta Analysis ◽

Evidence Based ◽

Pharmacologic Treatment ◽

Combination Treatments ◽

Second Generation Antipsychotics ◽

Improve Measurement ◽

Potential Drug Targets

During the last decade negative symptoms in schizophrenia became a legitimate indication for potential drug targets. Significant progress has been made to improve measurement of negative symptoms, to distinguish between primary and secondary negative symptoms, and the importance of predominant negative symptoms was underlined. However, few clinical trials focused on primary and/or predominant negative symptoms. A large meta-analysis found that second-generation antipsychotics (SGA) had the greatest efficacy for negative symptoms, followed by first-generation antipsychotics (FGA), combination treatments, antidepressants, and glutamatergic medications. The included studies, however, were not specifically designed to measure negative symptoms. With respect to patients with predominant negative symptoms, in the largest trial conducted so far, the SGA cariprazine was superior to its comparator, risperidone. For medication classes other than antipsychotics and antidepressants, no reliable support was found that would substantiate evidence-based recommendations for using these agents in the treatment of negative symptoms in clinical practice.

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Structural evidence for the binding of monocarboxylates and dicarboxylates at pharmacologically relevant extracellular sites of a pentameric ligand-gated ion channel

Acta Crystallographica Section D Structural Biology ◽

10.1107/s205979832000772x ◽

2020 ◽

Vol 76 (7) ◽

pp. 668-675 ◽

Cited By ~ 1

Author(s):

Zaineb Fourati ◽

Ludovic Sauguet ◽

Marc Delarue

Keyword(s):

Ion Channels ◽

Carboxylic Acid ◽

Experimental Evidence ◽

Binding Sites ◽

Drug Targets ◽

Allosteric Modulation ◽

Potential Drug ◽

X Ray ◽

Potential Drug Targets ◽

Fast Chemical

GLIC is a bacterial homologue of the pentameric ligand-gated ion channels (pLGICs) that mediate the fast chemical neurotransmission of nerve signalling in eukaryotes. Because the activation and allosteric modulation features are conserved among prokaryotic and eukaryotic pLGICs, GLIC is commonly used as a model to study the allosteric transition and structural pharmacology of pLGICs. It has previously been shown that GLIC is inhibited by some carboxylic acid derivatives. Here, experimental evidence for carboxylate binding to GLIC is provided by solving its X-ray structures with a series of monocarboxylate and dicarboxylate derivatives, and two carboxylate-binding sites are described: (i) the `intersubunit' site that partially overlaps the canonical pLGIC orthosteric site and (ii) the `intrasubunit' vestibular site, which is only occupied by a subset of the described derivatives. While the intersubunit site is widely conserved in all pLGICs, the intrasubunit site is only conserved in cationic eukaryotic pLGICs. This study sheds light on the importance of these two extracellular modulation sites as potential drug targets in pLGICs.

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