Biology subjects

Kim, Y.-C.

Publications and source records attributed to Kim, Y.-C..

5 recordsLinked to original sources

bioRxiv2025

UB-MBX-46 is a potent and selective antagonist of the human P2X7 receptor developed by structure-based drug design

The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Interspecies variation among existing antagonists has proven challenging, in part due to the dearth of molecular information on different receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with new and existing structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with picomolar potency and high selectivity, revealing its significant therapeutic potential.

biochemistry↗

bioRxiv2023

SECRET AGENT O-GlcNAc Modifies GIGANTEA: Methods for Mapping of O-Linked β-N-Acetylglucosamine Modification Sites Using Mass Spectrometry

Arabidopsis thaliana has two glycosyl transferases, SPINDLY (SPY) and SECRET AGENT (SEC), that modify nuclear and cytosolic protein with O-linked fucose and N-acetylglucosamine (GlcNAc), respectively. SPY interacts physically and genetically with GIGANTEA (GI). Previously, we reported that SEC substrates are O-GlcNAc modified when they are co-expressed in E. coli. By analyzing overlapping sub-fragments of GI, we found a region that was modified by SEC. Mutational mapping of the modified region was then performed. Modification was undetectable when threonine 829 was mutated to alanine (T829A) while the T834A and T837A mutations reduced modification suggesting that T829 was the primary or only modification site. Mapping using several enrichment and mass spectrometry methods all detected only modification of T829.

plant biology↗

bioRxiv2022

Predicting Lung Cancer in Korean Never-Smokers with Polygenic Risk Scores

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer. Hence, recently, genetic data have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs). PRSs were calculated using a thresholding-pruning-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31-2.23), and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747-0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLongs test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.

bioinformatics↗

bioRxiv2020

Protective effect of agmatine against cisplatin-induced apoptosis in an auditory cell line

ObjectivesAgmatine, an endogenous metabolite of arginine, is known to have antioxidant activity, protect mitochondrial function, and confer resistance to cellular apoptosis. The aim of this study was to evaluate the protective effects of agmatine against cisplatin-induced cellular apoptosis in an auditory cell line. MethodsHEI-OC1 cells were co-treated with agmatine at different concentrations and 15 {micro}M cisplatin for 48 h. Cell viability was measured and annexin V-FITC/propidium iodide (PI) staining was performed to analyze apoptosis. The levels of intracellular reactive oxygen species (ROS) were measured using flow cytometry. The expression of BAX (Bcl2-associated X protein) and the enzymatic activity of caspase-3 were measured to examine the pathway of apoptosis induction. ResultsCo-treatment with 8 mM agmatine protected HEI-OC1 cells against cisplatin-induced cell apoptosis. Agmatine exerted a significant protective effect against 15 {micro}M cisplatin when applied for 48 h and reduced the proportion of necrotic and late apoptotic cells. Agmatine did not reduce the cisplatin-induced increase in ROS but decreased the expression of BAX and the activity of caspase-3. ConclusionsAgmatine protected against cisplatin-induced cellular apoptosis in an auditory cell line. These effects were mediated by the protection of mitochondrial function and inhibition of apoptosis.

pharmacology and toxicology↗

bioRxiv2017

Prefrontal D1 dopamine-receptor neurons and delta resonance in interval timing

Considerable evidence has shown that prefrontal neurons expressing D1-type dopamine receptors (D1DRs) are critical for working memory, flexibility, and timing. This line of work predicts that frontal neurons expressing D1DRs mediate cognitive processing. During timing tasks, one form this cognitive processing might take is time-dependent ramping activity -- monotonic changes in firing rate over time. Thus, we hypothesized the prefrontal D1DR+ neurons would strongly exhibited time-dependent ramping during interval timing. We tested this idea using an interval-timing task in which we used optogenetics to tag D1DR+ neurons in the mouse medial frontal cortex (MFC). While 23% of MFC D1DR+ neurons exhibited ramping, this was significantly less than untagged MFC D1DR+ neurons. By contrast, MFC D1DR+ neurons had strong delta-frequency (1-4 Hz) coherence with other MFC ramping neurons. This coherence was phase-locked to cue onset and was strongest early in the interval. To test the significance of these interactions, we optogenetically stimulated MFC D1DR+ neurons early vs. late in the interval. We found that 2-Hz stimulation early in the interval was particularly effective in rescuing timing-related behavioral performance deficits in dopamine-depleted animals. These findings provide insight into MFC networks and have relevance for disorders such as Parkinsons disease and schizophrenia.\n\nSignificance StatementPrefrontal D1DRs are involved in cognitive processing and cognitive dysfunction in human diseases such as Parkinsons disease and schizophrenia. We use optogenetics to identify these neurons, as well as neurons that are putatively connected to MFC D1DR+ neurons. We study these neurons in detail during an elementary cognitive task. These data could have relevance for cognitive deficits for Parkinsons disease, schizophrenia, and other diseases involving frontal dopamine.

neuroscience↗