• YAKHAK HOEJI
• /
• v.47 no.3
• /
• pp.180-183
• /
• 2003

Crystal structure of TRAF6 in complex with TRAF6-binding sites from CD40 was previously determined. The structure revealed a distinct TRAF6-binding groove of CD40, the key structural determinant of interaction. The structural information leads to a proposed TRAF6-binding motif. This allows the identification of TRAF6-binding sequences in the hIRAK protein, whose functional requirement in IL-1/Toll-like receptor superfamilies-mediated signal transduction is further demonstrated using site-directed mutagenesis. The mutational effects of hIRAK on the down-stream NF-kB signaling shows the importance of the TRAF6 interface for signaling by IL-1/Toll-like receptor superfamilies.

• Journal of Integrative Natural Science
• /
• v.10 no.1
• /
• pp.14-19
• /
• 2017

Neuromedin, a neuropeptide, which is involved in various functions that include contractile activity on smooth muscle, controlling the blood flow and ion transport in the intestine, increased blood pressure and regulation of adrenocortical function. It is involved in the pathophysiology of various immune mediated inflammatory diseases like asthma. In this study, we have performed protein-protein docking analysis of neuromedin U - neuromedin U receptor 1 complex. We have developed homology models of neuromedin U, and selected a reliable model using model validation. The model was docked with the receptor model, to analyse the crucial interactions of the complex. This study could be helpful as a tool in developing novel and potent drugs for the diseases related with neuromedin U receptor 1.

• Proceedings of the PSK Conference
• /
• 2003.10b
• /
• pp.77.2-77.2
• /
• 2003

The dopamine D2 receptor (D$_2$R) is target for antipsychotic drugs and associated with several neuropsychiatric disorders. The internalization (sequestration) of G protin-coupled receptor is caused by agonist-induced receptor phosphorylation mediated by GRK, followed by the interaction with ${\beta}$-arrestin. In this study, we examined the agonist-dependent sequestration/internalization of dopamine D$_2$R, which were transiently expressed in HEK 293 cells with of without GRK co-expression. Co-expression of GRK2 or GRK3 markedly enhanced the sequestration of D$_2$R. (omitted)

• Archives of Pharmacal Research
• /
• v.22 no.2
• /
• pp.113-118
• /
• 1999

Previous work in our laboratory has shown that the N-methyl-D-aspartate (NMDA) receptor antagonists, AP-5, CPP, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced enhancement of 5-hydroxytryptamine (5-HT)-induced head-twitch response (HTR) in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of serotonergic function at the postsynaptic $5-HT_{2}$ receptors. The purpose of this study was to extend our previous work on the behavioral interaction between glutamatergic and serotonergic receptors. In the present study, both competitive (AP-5 and CPP) and noncompeti-tive (MI-801, ketamine, dextrorphan and dextromethorphan) NMDA receptor antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, in p-chlorophenylalanine (PCPA)-treated mice which were devoid of any involvement of indirect serotonergic function, to establish the involvement of the NMDA receptor in 5-HT-induced HTR at the postsyaptic $5-HT_{2}$receptors. In addition, the enhancement of 5-HT-induced HTR was inhibited by a dopamine agonist, apomorphine, NMDA receptor antagonist, NMDA and a serotonin $5-HT_{2}$receptor antagonist, cyproheptadine, in PCPA-treated mice. Therefore, the present results support our previous conclusion that the NMDA receptors play an important role in the glutamatergic modulation of serotonergic function at the poststynaptic $5-HT_{2}$ receptors.

• 대한핵의학회:학술대회논문집
• /
• 2001.05a
• /
• pp.56-59
• /
• 2001

• Clinical Nutrition Research
• /
• v.13 no.3
• /
• pp.214-225
• /
• 2024

Polymorphisms in the melanocortin 4 receptor (MC4R) gene with occurrence and progression of chronic diseases such as obesity and cardiovascular disease (CVD) have long been addressed but there is a lack of evidence for complex interrelationships, including direct and indirect effects of these variables. This review specifically focuses on studying the effects of healthy diet interaction and MC4R polymorphisms on the development of CVD. The quantity and quality of carbohydrates and proteins consumed are related to obesity susceptibility and cardiometabolic risk factors. A healthy dietary pattern such as a Mediterranean dietary can modulate the association between MC4R polymorphisms (rs17782313) and the risk of CVDs. Also, the Nordic diet can reduce lipid profiles such as low-density lipoprotein cholesterol (LDL-C) and total cholesterol levels. On the other hand, MC4R interaction with the dietary inflammatory index decreases high-density lipoprotein cholesterol levels and increases LDL-C and triglyceride (TG) levels. Additionally, the DASH diet decreases TG, atherogenic index of plasma, systolic blood pressure, diastolic blood pressure, and serum glucose. The interaction between MC4R genes and diets plays an important role in the development of CVD. Adherence to healthy diets such as the Mediterranean, Nordic, Anti-inflammatory, and Dash diets might be an efficient strategy to prevent CVD. The potential for personalized diets to be developed for the treatment and prevention of CVD and its related comorbidities is expected to expand as this field develops.

• Journal of Integrative Natural Science
• /
• v.5 no.1
• /
• pp.32-37
• /
• 2012

Chemokine receptor antagonists have potential applications in field of drug discovery. Although the chemokine receptors are G-protein-coupled receptors, their cognate ligands are small proteins (8 to 12 kDa), and so inhibiting the ligand/receptor interaction has been challenging. The application of structure-based in-silico methods to drug discovery is still considered a major challenge, especially when the x-ray structure of the target protein is unknown. Such is the case with human CCR2 and CCR5, the most important members of the chemokine receptor family and also a potential drug target. Herein, we review the success stories of combined receptor modeling/mutagenesis approach to probe the allosteric nature of chemokine receptor binding by small molecule antagonists for CCR2 and CCR5 using Rhodopsin as template. We also urged the importance of recently available ${\beta}2$-andrenergic receptor as an alternate template to guide mutagenesis. The results demonstrate the usefulness and robustness of in-silico 3D models. These models could also be useful for the design of novel and potent CCR2 and CCR5 antagonists using structure based drug design.

• Molecules and Cells
• /
• v.41 no.9
• /
• pp.842-852
• /
• 2018

Notch signaling is an evolutionarily conserved pathway and involves in the regulation of various cellular and developmental processes. Ligand binding releases the intracellular domain of Notch receptor (NICD), which interacts with DNA-bound CSL [CBF1/Su(H)/Lag-1] to activate transcription of target genes. In the absence of NICD binding, CSL down-regulates target gene expression through the recruitment of various corepressor proteins including SMRT/NCoR (silencing mediator of retinoid and thyroid receptors/nuclear receptor corepressor), SHARP (SMRT/HDAC1-associated repressor protein), and KyoT2. Structural and functional studies revealed the molecular basis of these interactions, in which NICD coactivator and corepressor proteins competitively bind to ${\beta}-trefoil$ domain (BTD) of CSL using a conserved ${\varphi}W{\varphi}P$ motif (${\varphi}$ denotes any hydrophobic residues). To date, there are conflicting ideas regarding the molecular mechanism of SMRT-mediated repression of CSL as to whether CSL-SMRT interaction is direct or indirect (via the bridge factor SHARP). To solve this issue, we mapped the CSL-binding region of SMRT and employed a 'one- plus two-hybrid system' to obtain CSL interaction-defective mutants for this region. We identified the CSL-interaction module of SMRT (CIMS; amino acid 1816-1846) as the molecular determinant of its direct interaction with CSL. Notably, CIMS contains a canonical ${\varphi}W{\varphi}P$ sequence (APIWRP, amino acids 1832-1837) and directly interacts with CSL-BTD in a mode similar to other BTD-binding corepressors. Finally, we showed that CSL-interaction motif, rather than SHARP-interaction motif, of SMRT is involved in transcriptional repression of NICD in a cell-based assay. These results strongly suggest that SMRT participates in CSL-mediated repression via direct binding to CSL.

• The Korean Journal of Physiology and Pharmacology
• /
• v.24 no.1
• /
• pp.101-110
• /
• 2020

Transient receptor potential canonical 4 (TRPC4) channel is a nonselective calcium-permeable cation channels. In intestinal smooth muscle cells, TRPC4 currents contribute more than 80% to muscarinic cationic current (mIcat). With its inward-rectifying current-voltage relationship and high calcium permeability, TRPC4 channels permit calcium influx once the channel is opened by muscarinic receptor stimulation. Polyamines are known to inhibit nonselective cation channels that mediate the generation of mIcat. Moreover, it is reported that TRPC4 channels are blocked by the intracellular spermine through electrostatic interaction with glutamate residues (E728, E729). Here, we investigated the correlation between the magnitude of channel inactivation by spermine and the magnitude of channel conductance. We also found additional spermine binding sites in TRPC4. We evaluated channel activity with electrophysiological recordings and revalidated structural significance based on Cryo-EM structure, which was resolved recently. We found that there is no correlation between magnitude of inhibitory action of spermine and magnitude of maximum current of the channel. In intracellular region, TRPC4 attracts spermine at channel periphery by reducing access resistance, and acidic residues contribute to blocking action of intracellular spermine; channel periphery, E649; cytosolic space, D629, D649, and E687.

• Bulletin of the Korean Chemical Society
• /
• v.29 no.8
• /
• pp.1499-1504
• /
• 2008

Pyrazine derivatives bind to b-RAF receptor which is important in cancer therapy. The ligand-receptor interactions have been studied by comparative molecular field analysis (CoMFA) and molecular docking methods. Applying conventional ligand-based alignment schemes for the whole set was not successful. However, QM and DFT results suggested that some ligands have electrostatic interaction while others have steric interactions. On the basis of these results, we divided the dataset into two subsets. Electrostatic effect was found to be important in one set while steric effect for the other. Best docking modes were obtained for each subset based on the available crystal structure. These receptor-guided CoMFA models propose an interesting possibility which is difficult to obtain otherwise. i.e., in one binding mode the electrostatic interaction plays a key role for one subset ($q^2$ = 0.46, $r^2$ = 0.98), while in another binding mode steric effect is important with another subset ($q^2$ = 0.43, $r^2$ = 0.74).