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Kim, Su Jin,Cho, Jinhong,Song, Eun Joo,Kim, Soo Jin,Kim, Ho Min,Lee, Kyung Eun,Suh, Se Won,Kim, Eunice EunKyeong American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.18
<P>Valosin-containing protein (VCP), also known as p97, is an AAA<SUP>+</SUP> ATPase that plays an essential role in a broad array of cellular processes including the endoplasmic reticulum-associated degradation (ERAD) pathway. Recently, ERAD-specific deubiquitinating enzymes have been reported to be physically associated with VCP, although the exact mechanism is not yet clear. Among these enzymes is ovarian tumor domain-containing protein 1 (OTU1). Here, we report the structural basis for interaction between VCP and OTU1. The crystal structure of the ubiquitin regulatory X-like (UBXL) domain of OTU1 (UBXL<SUB>OTU1</SUB>) complexed to the N-terminal domain of VCP (N<SUB>VCP</SUB>) at 1.8-Å resolution reveals that UBXL<SUB>OTU1</SUB> adopts a ubiquitin-like fold and binds at the interface of two subdomains of N<SUB>VCP</SUB> using the <SUP>39</SUP>GYPP<SUP>42</SUP> loop of UBXL<SUB>OTU1</SUB> with the two prolines in <I>cis</I>- and <I>trans</I>-configurations, respectively. A mutagenesis study shows that this loop is not only critical for the interaction with VCP but also for its role in the ERAD pathway. Negative staining EM shows that one molecule of OTU1 binds to one VCP hexamer, and isothermal titration calorimetry suggests that the two proteins bind with a <I>K<SUB>D</SUB></I> of 0.71 μ<SMALL>m</SMALL>. Analytical size exclusion chromatography and isothermal titration calorimetry demonstrates that OTU1 can bind VCP in both the presence and absence of a heterodimer formed by ubiquitin fusion degradation protein 1 and nuclear localization protein 4.</P>
Eunkyeong Park,Hyungsoo Kim,Jongjoo Shim,Yong-Ju Kim,Yun-Saing Kim,Jingook Kim [Institute of Electrical and Electronics Engineers 2015 IEEE transactions on electromagnetic compatibility Vol.57 No.4
<P>The jitter probability density function (PDF) at multistage output buffers due to supply voltage fluctuations is analytically derived. For experimental validation, an integrated circuit (IC) is designed, fabricated, and assembled in a printed circuit board (PCB). The on-chip supply voltage fluctuations are extracted from the simultaneous measurements at the pads on IC and PCB and used to calculate the jitter PDF of the multistage buffers. Also, characteristics of the output channels are measured and modeled with the separately designed channel pattern. Finally, the jitter PDFs for multistage buffers are calculated and compared with the measured jitter histograms.</P>
Toll-like Receptor 2 Senses β-Cell Death and Contributes to the Initiation of Autoimmune Diabetes
Kim, Hun Sik,Han, Myoung Sook,Chung, Kun Wook,Kim, Sunshin,Kim, Eunshil,Kim, Myoung Joo,Jang, Eunkyeong,Lee, Hyun Ah,Youn, Jeehee,Akira, Shizuo,Lee, Myung-Shik Elsevier 2007 Immunity Vol.27 No.2
<P><B>Summary</B></P><P>Although it is established that defective clearance and, hence, increased accumulation of apoptotic cells can lead to autoimmunity, the mechanism by which this occurs remains elusive. Here, we observed that apoptotic cells undergoing secondary necrosis but not intact apoptotic cells provoked substantial immune responses, which were mediated through the toll-like receptor 2 (TLR2) pathway. The development of autoimmune diabetes was markedly inhibited in <I>Tlr2<SUP>−/−</SUP></I> mice but not in <I>Tlr4<SUP>−/−</SUP></I> mice, showing that TLR2 plays an important role in the initiation of the disease. Apoptotic β-cell injury could stimulate the priming of diabetogenic T cells through a TLR2-dependent, but TLR4-independent, activation of antigen-presenting cells. These findings suggest that β-cell death and its sensing via TLR2 may be an initial event for the stimulation of antigen-presenting cells and development of autoimmune diabetes.</P>
Unique binding mode of Evogliptin with human dipeptidyl peptidase IV
Lee, Hyung Ki,Kim, Mi-Kyung,Kim, Ha Dong,Kim, Heung Jae,Kim, Ji Won,Lee, Jie-Oh,Kim, Chan-Wha,Kim, Eunice EunKyeong Elsevier 2017 Biochemical and biophysical research communication Vol. No.
<P><B>Abstract</B></P> <P>Evogliptin ((<I>R</I>)-4-((<I>R</I>)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(<I>tert-</I>butoxymethyl) piperazine-2-one)) is a highly potent selective inhibitor of dipeptidyl peptidase IV (DPP4) that was approved for the treatment of type 2 diabetes in South Korea. In this study, we report the crystal structures of Evogliptin, DA-12166, and DA-12228 (<I>S,R</I> diastereomer of Evogliptin) complexed to human DPP4. Analysis of both the structures and inhibitory activities suggests that the binding of the trifluorophenyl moiety in the S<SUB>1</SUB> pocket and the piperazine-2-one moiety have hydrophobic interactions with Phe357 in the S<SUB>2</SUB> extensive subsite, and that the multiple hydrogen bonds made by the (<I>R</I>)-β-amine group in the S<SUB>2</SUB> pocket and the contacts made by the (<I>R</I>)-<I>tert</I>-butyl group with Arg125 contribute to the high potency observed for Evogliptin.</P>
Kim, Seung Min,Shin, Sang Chul,Kim, Eunice EunKyeong,Kim, Sang-Heon,Park, Kwideok,Oh, Seung Ja,Jang, Mihue American Chemical Society 2018 ACS NANO Vol.12 No.8
<P>Cas9 ribonucleoprotein (RNP)-mediated delivery has emerged as an ideal approach for <I>in vivo</I> applications. However, the delivery of Cas9 RNPs requires electroporation or lipid- or cationic-reagent-mediated transfection. Here, we developed a carrier-free Cas9 RNP delivery system for robust gene editing <I>in vivo</I>. For simultaneous delivery of Cas9 and a guide RNA into target cells without the aid of any transfection reagents, we established a multifunctional Cas9 fusion protein (Cas9-LMWP) that forms a ternary complex with synthetic crRNA:tracrRNA hybrids in a simple procedure. Cas9-LMWP carrying both a nuclear localization sequence and a low-molecular-weight protamine (LMWP) enables the direct self-assembly of a Cas9:crRNA:tracrRNA ternary complex (a ternary Cas9 RNP) and allows for the delivery of the ternary Cas9 RNPs into the recipient cells, owing to its intrinsic cellular and nuclear translocation ability with low immunogenicity. To demonstrate the potential of this system, we showed extensive synergistic anti-KRAS therapy (CI value: 0.34) <I>via in vitro</I> and <I>in vivo</I> editing of the <I>KRAS</I> gene by the direct delivery of multifunctional Cas9 RNPs in lung cancer. Thus, our carrier-free Cas9 RNP delivery system could be an innovative platform that might serve as an alternative to conventional transfection reagents for simple gene editing and high-throughput genetic screening.</P> [FIG OMISSION]</BR>
Kim, Kook-Han,Lee, Won-Kyu,Choi, Kyung-Jae,Kim, Eunice EunKyeong The Korean Society for Applied Biological Chemistr 2014 Applied Biological Chemistry (Appl Biol Chem) Vol.57 No.5
Bacterial resistance to many existing antibiotics is a growing health concern worldwide. There is an urgent need to identify new antibiotics with unexploited modes of action. Peptide deformylase (PDF) is an essential enzyme involved in N-terminal protein processing in eubacteria but not in higher organisms. Therefore, PDF is considered an attractive target for the development of novel antibiotics. Here, we report the structures of the PDFs from Enterococcus faecalis (EfPDF) and Streptococcus pyogenes (SpyPDF) complexed with actinonin at 1.4 and $2.1{\AA}$ resolutions, respectively. Actinonin, a naturally occurring, highly potent inhibitor, is bound tightly at the active site. The conformation of actinonin in the EfPDF and SpyPDF complexes was similar to those of all others. The detailed information from this study will facilitate the development of novel antibacterial molecules.
Kim, Young Kwan,Mizutani, Kenji,Rhee, Kyung-Hee,Nam, Ki-Hyun,Lee, Won Ho,Lee, Eun Hye,Kim, Eunice Eunkyeong,Park, Sam-Yong,Hwang, Kwang Yeon American Society for Microbiology 2007 Journal of Bacteriology Vol.189 No.22
<B>ABSTRACT</B><P>In archaea, RNA endonucleases that act specifically on RNA with bulge-helix-bulge motifs play the main role in the recognition and excision of introns, while the eukaryal enzymes use a measuring mechanism to determine the positions of the universally positioned splice sites relative to the conserved domain of pre-tRNA. Two crystallographic structures of tRNA intron-splicing endonuclease from <I>Thermoplasma acidophilum</I> DSM 1728 (EndA<I>Ta</I>) have been solved to 2.5-Å and 2.7-Å resolution by molecular replacement, using the 2.7-Å resolution data as the initial model and the single-wavelength anomalous-dispersion phasing method using selenomethionine as anomalous signals, respectively. The models show that EndA<I>Ta</I> is a homodimer and that it has overall folding similar to that of other archaeal tRNA endonucleases. From structural and mutational analyses of H236A, Y229F, and K265I in vitro, we have demonstrated that they play critical roles in recognizing the splice site and in cleaving the pre-tRNA substrate.</P>
Temperament and Character of High Suicide Risk Group Among Psychiatric Patients
Kim Kyungwon,Park Yong Chon,Choi Junho,Kim Daeho,Kim Eunkyeong 대한신경정신의학회 2022 PSYCHIATRY INVESTIGATION Vol.19 No.8
Objective The purpose of this study was to classify patients with suicidal tendencies into suicide attempts (SA), suicidal ideation (SI), and non-suicidal self-injury (NSSI) and to identify differences in temperaments and characters of the groups. It also aimed to identify difference between the groups and non-suicidal tendencies.Methods Using psychiatric diagnostic data of 195 patients, temperaments and characters were measured with the Temperament and Character Inventory, and the level of depression was measured with the Beck Depression Inventory. The subjects were classified into SA, SI, NSSI, psychiatric patients without suicidal tendencies (PP), and non-patient (Normal) groups, and multivariate analysis of variance and multinomial logistic regression were conducted.Results The NSSI group had higher novelty seeking compared to the SI group, while having higher harm avoidance, lower persistence, and lower self-directedness compared to the SA group. Furthermore, low persistence was a better predictor for the SA group between SA and NSSI groups, and low novelty seeking was found to be a better predictor for the SI group between the SI and NSSI groups.Conclusion As a result, the group differences in temperaments and characters were found, which would be useful to identify patients with suicidal tendencies and provide appropriate interventions tailored to the temperaments and characters of each group.
Jang, Eunkyeong,Kim, Hong Ro,Cho, Sin Hye,Paik, Doo-Jin,Kim, Jung Mogg,Lee, Sang-Koo,Youn, Jeehee Wiley Subscription Services, Inc., A Wiley Company 2006 Vol.54 No.2
<B>Objective</B><P>K/BxN-transgenic mice are a model of autoimmune arthritis, similar to rheumatoid arthritis. This study was undertaken to determine whether inhibition of lymphopenia-provoked homeostatic expansion can prevent spontaneous development of disease in the K/BxN model.</P><B>Methods</B><P>To inhibit homeostatic expansion of autoreactive T cells, K/BxN mice with disease in the preclinical stage were adoptively transferred with CD4+ T cells purified from nontransgenic BxN or Thy1.1+ BxN mice. To observe the profile of proliferation of CD4+ T cells derived from the hosts, carboxyfluorescein diacetate succinimidyl ester–labeled autologous CD4+ T cells were cotransferred to K/BxN mice together with BxN CD4+ T cells. Disease onset and progression were scored, and the dynamics and phenotypes of recipient CD4+ T cells were determined by flow cytometry, before and after cell infusion.</P><B>Results</B><P>During the preclinical phase of disease, K/BxN mice exhibited CD4+ T lymphopenia, which was followed by a compensatory expansion of these cells during the early clinical phase. The majority of CD4+ T cells acquired a memory phenotype (CD44<SUP>high</SUP>,CD62L<SUP>low</SUP>,CD25−), which is a hallmark of homeostatically expanding cells. Importantly, K/BxN mice subjected to syngeneic T cell transfer did not develop symptoms of arthritis and also possessed fewer transgenic T cell receptor–encoded V<SUB>β</SUB>6+,CD4+ T cells. This effect was associated with decreased proliferation of recipient-derived CD4+ T cells but not with the function of CD25+ T regulatory cells present in donor cells.</P><B>Conclusion</B><P>These results provide the first evidence that lymphopenia-associated homeostatic proliferation of autoreactive CD4+ T cells potentiates autoimmune arthritis, and that inhibition of this process protects mice from the development of this pathologic condition.</P>