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- 검색키워드
- 저자 : Yoonji Lee (검색결과 105 건)
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Lee, Yoonji,Min, Kyunghun,Son, Hokyoung,Park, Ae Ran,Kim, Jin-Cheol,Choi, Gyung Ja,Lee, Yin-Won APS Press 2014 Molecular plant-microbe interactions Vol.27 No.12
<P>Fusarium graminearum is an important fungal plant pathogen that causes serious losses in cereal crop yields and mycotoxicoses in humans and livestock. In this study, we characterized an insertion mutant, Z39R9282, with pleiotropic defects in sexual development and virulence. We determined that the insertion occurred in a gene encoding an ortholog of yeast elongator complex protein 3 (ELP3). Deletion of elp3 led to significant defects in sexual and asexual development in F. graminearum. In the elp3 deletion mutant, the number of perithecia formed was reduced and maturation of perithecia was delayed. This mutant also produced morphologically abnormal ascospores and conidia. Histone acetylation in the elp3 deletion mutant was reduced compared with the wild type, which likely caused the developmental defects. Trichothecenes were not produced at detectable levels, and expression of trichothecene biosynthesis genes were significantly reduced in the elp3 deletion mutant. Infection of wheat heads revealed that the elp3 deletion mutant was unable to spread from inoculated florets to neighboring spikelets. Furthermore, the elp3 deletion mutant was more sensitive to oxidative stress than the wild type, and the expression of putative catalase genes was reduced. We demonstrate that elp3 functions in sexual and asexual development, virulence, and the oxidative stress response of F. graminearum by regulating the expression of genes involved in these various developmental processes.</P>
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Transient receptor potential vanilloid type 1 antagonists: a patent review (2011 - 2014)
Lee, Yoonji,Hong, Sunhye,Cui, Minghua,Sharma, Pankaz K,Lee, Jeewoo,Choi, Sun Informa UK, Ltd. 2015 Expert opinion on therapeutic patents Vol.25 No.3
<P>Introduction: Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel that can be activated by noxious heat, low pH and vanilloid compounds such as capsaicin. Since TRPV1 acts as an integrator of painful stimuli, TRPV1 antagonists can be used as promising therapeutics for new types of analgesics. Areas covered: This review article covers the patents that claim TRPV1 antagonists and were published during 2011 - 2014. The patent evaluation is organized according to the applicant companies, and the representative chemical entities with important in vitro and in vivo data are summarized. Expert opinion: Many pharmaceutical companies showed promising results in the discovery of potent small molecule TRPV1 antagonists, and recently, a number of small molecule TRPV1 antagonists have been advanced into clinical trials. Unfortunately, several candidate molecules showed critical side effects such as hyperthermia and impaired noxious heat sensation in humans, leading to their withdrawal from clinical trials. Some TRPV1 antagonists patented in recent years (2011 - 2014) overcame these undesirable side effects, making the development of TRPV1 antagonists much more promising.</P>
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Lee, Yoonji,Choi, Sun,Hyeon, Changbong Public Library of Science 2015 PLoS computational biology Vol.11 No.2
<▼1><P>Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ~ 5 μsec molecular dynamics simulations of A<SUB>2A</SUB> adenosine receptor (A<SUB>2A</SUB>AR) in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs “binary switches” as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield 2<SUP>10</SUP> microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation. Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.</P></▼1><▼2><P><B>Author Summary</B></P><P>As the key signal transmitters of a number of physiological processes, G-protein coupled receptors (GPCRs) are arguably one of the most important therapeutic targets. Orchestration of the intra-molecular signaling across transmembrane domain is key for the function of GPCRs. To investigate the microscopic underpinnings of intramolecular signaling that regulates the activation of GPCRs, we performed molecular dynamics simulations of the receptor in three distinct ligand-bound states using A<SUB>2<I>A</I></SUB> adenosine receptor as a model system of GPCRs. Statistical analyses on the dynamics of and correlation among the 10 “binary switches” reveal that the three receptor states retain distinct dynamic properties. The antagonist- and agonist-bound forms of the receptors explore vastly different conformational space, and the apo form lies between them, yet located closer to the antagonist-bound form. In regard to the agonist-binding triggered activation mechanism, the correlation map among the 10 binary switches unequivocally shows that direct sensing of agonist ligand by the indole ring of W246 actuates the rest of intramolecular signaling.</P></▼2>
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Lee, Jin Hee,Lee, Yoonji,Ryu, HyungChul,Kang, Dong Wook,Lee, Jeewoo,Lazar, Jozsef,Pearce, Larry V,Pavlyukovets, Vladimir A,Blumberg, Peter M,Choi, Sun ESCOM ; Kluwer Academic Publishers 2011 Journal of computer-aided molecular design Vol.25 No.4
<P>The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.</P>
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3D-QSAR studies of cytotoxic heterocyclic quinones using calculated reduction potential
Lee, Yoonji,Kim, Seoeun,Rhee, Hee-Kyung,Doh, Kyung-Eun,Park, Junhee,Lee, Chong-Ock,Choi, Sun,Choo, Hea-Young Park Wiley Subscription Services, Inc., A Wiley Company 2009 Drug development research Vol.70 No.6
<P>Most quinones with 2–4 fused aromatic rings exhibit cytostatic activity via DNA intercalation that causes enzyme blockade and reading errors during the replication process. The redox activity of quinones plays a role in the DNA cleavage mediated by oxygen or sulfur radicals. To develop novel anticancer agents based on nitrogen-containing heterocyclic quinones, pharmacophore models of representative molecules with high activity were generated using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). A series of compounds were aligned to the selected pharmacophore model and the 3D-quantitative structure activity relationships (QSAR) were analyzed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), resulting in q<SUP>2</SUP> values of 0.734 and r<SUP>2</SUP> of 0.951, and q<SUP>2</SUP> of 0.803 and r<SUP>2</SUP> of 0.917, respectively, in each study. In addition, the potentials for the one-electron reduction of quinones were calculated from LUMO energies using the semi-empirical Austin Model 1 (AM1) method. These also showed a good correlation (r<SUP>2</SUP> of 0.816) with the cytotoxic activities of the quinones. Drug Dev Res 2009. © 2009 Wiley-Liss, Inc.</P>
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Irisin, a Novel Myokine, Regulates Glucose Uptake in Skeletal Muscle Cells via AMPK
Lee, Hye Jeong,Lee, Jung Ok,Kim, Nami,Kim, Joong Kwan,Kim, Hyung Ip,Lee, Yong Woo,Kim, Su Jin,Choi, Jong-Il,Oh, Yoonji,Kim, Jeong Hyun,Hwang, Suyeon-,Park, Sun Hwa,Kim, Hyeon Soo Endocrine Society 2015 Molecular endocrinology Vol.29 No.6
<P>Irisin is a novel myokine produced by skeletal muscle. However, its metabolic role is poorly understood. In the present study, irisin induced glucose uptake in differentiated skeletal muscle cells. It increased AMP-activated protein kinase (AMPK) phosphorylation and the inhibition of AMPK blocked glucose uptake. It also increased reactive oxygen species (ROS) generation. N-acetyl cysteine, a ROS scavenger, blocked irisin-induced AMPK phosphorylation. Moreover, irisin activated p38 MAPK in an AMPK-dependent manner. The inhibition and knockdown of p38 MAPK blocked irisin-induced glucose uptake. A colorimetric absorbance assay showed that irisin stimulated the translocation of glucose transporter type 4 to the plasma membrane and that this effect was suppressed in cells pretreated with a p38 MAPK inhibitor or p38 MAPK small interfering RNA. In primary cultured myoblast cells, irisin increased the concentration of intracellular calcium. STO-609, a calcium/calmodulin-dependent protein kinase kinase inhibitor, blocked irisin-induced AMPK phosphorylation, implying that calcium is involved in irisin-mediated signaling. Our results suggest that irisin plays an important role in glucose metabolism via the ROS-mediated AMPK pathway in skeletal muscle cells.</P>
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Lee, Yoonji,Jeong, Lak Shin,Choi, Sun,Hyeon, Changbong American Chemical Society 2011 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.133 No.49
<P><I>S</I>-adenosylhomocysteine hydrolase (SAHH), a cellular enzyme that plays a key role in methylation reactions including those required for maturation of viral mRNA, is an important drug target in the discovery of antiviral agents. While targeting the active site is a straightforward strategy of enzyme inhibition, evidence of allosteric modulation of active site in many enzymes underscores the molecular origin of signal transduction. Information of co-evolving sequences in SAHH family and the key residues for functional dynamics that can be identified using native topology of the enzyme provide glimpses into how the allosteric signaling network, dispersed over the molecular structure, coordinates intra- and intersubunit conformational dynamics. To study the link between the allosteric communication and functional dynamics of SAHHs, we performed Brownian dynamics simulations by building a coarse-grained model based on the holo and ligand-bound structures. The simulations of ligand-induced transition revealed that the signal of intrasubunit closure dynamics is transmitted to form intersubunit contacts, which in turn invoke a precise alignment of active site, followed by the dimer–dimer rotation that compacts the whole tetrameric structure. Further analyses of SAHH dynamics associated with ligand binding provided evidence of both induced fit and population shift mechanisms and also showed that the transition-state ensemble is akin to the ligand-bound state. Besides the formation of enzyme-ligand contacts at the active site, the allosteric couplings from the residues distal to the active site are vital to the enzymatic function.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2011/jacsat.2011.133.issue-49/ja2066175/production/images/medium/ja-2011-066175_0006.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja2066175'>ACS Electronic Supporting Info</A></P>
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