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Systemic Proteomics of Cellular Switch and Drug Development
Ryu, Seong Eon 이화여자대학교 세포신호전달연구센터 2007 고사리 세포신호전달 심포지움 Vol. No.9
To understand cellular functional switch as a whole, one has to obtain comprehensive information on structure, activity, modification and interaction of all proteins involved in the related signaling and metabolic pathways. Such information could be acquired through large scale analysis of individual components as well as studies on correlation among associated components. Especially, for the development of disease-specific and effective new therapeutic drugs, comprehensive understanding of disease-related cellular system and structure-function relationship of protein families is required. To this end, our research group is generating and analyzing quantitative information on dynamic proteome fluctuation during disease-related cellular death phenomena that involves protein expression level, modification and subcellular localization changes. In relation to this analysis, we are also carrying out protein family-wide structure-function studies on disease related protein families such as protein tyrosine phosphatases and other target proteins identified from the proteome analysis. The structure-function data provide critical information on design of selective regulators of each enzyme. The systematic consideration of cellular regulation as exemplified in our studies would help to find effective strategies towards the development of next-generation therapeutic drugs.
Structural mechanism of cellular redox switch proteins
Ryu, Seong-Eon 이화여자대학교 세포신호전달연구센터 2002 고사리 세포신호전달 심포지움 Vol. No.4
Reactive oxygen species(ROS) are produced as byproducts of aerobic respiration and toxic to cells. However, ROS are used also as crucial cellular messengers in growth factor signal transduction, brain function, immune response and apoptosis. Recent studies indicate that there are intricate intracellular networks linking harmful ROS production and critical cellular regulatory functions. The cellular responses to altered levels of ROS involve redox switch proteins whose activities are regulated by oxidation. We determined crystal structures of the prototype redox switch proteins, OxyR and Hsp33. For OxyR, we obtained the structures before(reduced form) and after(oxidized form) reaction with ROS. For Hsp33, we determined the structure in its constitutively active form and carried out a series of biochemical and mutational analyses to elucidate the switch. From the structures of OxyR and Hsp33, and subsequent biochemical and mutational studies, we were able to understand their redox switch principles that should be applicable to other redox switch proteins. We showed that ROS-mediated disulfide bond formation between distant cysteines lead to fundamental structural transitions within domain and between subunits. These structural transitions, which were unexpected and observed for the first time, support important and active roles of ROS in many important physiological processes.
Structure and design of broadly-neutralizing antibodies against HIV
Ryu, Seong Eon,Hendrickson, Wayne A. Springer-Verlag 2012 Molecules and cells Vol.34 No.3
<P>Since the discovery more than 30 years ago of human immunodeficiency virus (HIV) as the causative agent of the deadly disease, acquired immune deficiency disease (AIDS), there have been no efficient vaccines against the virus. For the infection of the virus, the HIV surface glycoprotein gp120 first recognizes the CD4 receptor on the target helper T-cell, which initiates HIV fusion with the target cell and, if unchecked, leads to destruction of the patient's immune system. Despite the difficulty of developing appropriate immune responses in HIV-infected individuals, patient sera often contain antibodies that have broad neutralization activity, indicating the possibility of immunological treatment and prevention. Recently, through extensive structural studies of neutralizing antibodies of HIV in complex with gp120, the critical mechanisms of broad neutralization against HIV have been elucidated. Based on these discoveries, the structure-aided designs of antibodies and novel scaffolds were performed to create extremely potent neutralizing antibodies against HIV. These new discoveries and advances shed light on the road to development of efficient immunological therapies against AIDS.</P>
Targeting allosteric sites for protein tyrosine phosphatase inhibition
Seong Eon Ryu,Seung Jun Kim 한국구조생물학회 2014 Biodesign Vol.2 No.3
Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of phosphorylated protein substrates during cell signaling processes. Although various PTPs have been implicated as drug targets for human diseases, there have been no examples of therapeutics that target PTPs. Conventionally, PTP inhibitor developments mainly targeted the active site pocket whose structural characteristics limited the discovery of optimal compounds with potency, selectivity and membrane permeability. Recent approaches for allosteric inhibition have shed light on the development of therapeutics that target PTPs, and three classes of allosteric sites were identified in different members of PTPs. In a receptor-type PTP (RPTP), CD45, a domain interface pocket was targeted for allosteric inhibition. In MKP-4 and DUSP6, the crevice regions generated by the opening of the flexible D-loop were identified as allosteric inhibition sites. In PTP1B, the C-terminal disordered regions were found to bind novel non-competitive inhibitors. The novel inhibitors targeting those allosteric sites showed remarkable target-selectivity, potency, and in vivo activity. Approaches for allosteric inhibition provide exciting opportunities for the development of new PTP-targeting therapeutics for the effective treatment of cancer, diabetes, immune disorders and central nervous system diseases.
Structural mechanism of disulphide bond-mediated redox switches.
Japanese Biochemical Society 2012 The Journal of biochemistry Vol.151 No.6
<P>The oxidation of cysteine sulphydryl in proteins produces sulphenic acid that can form a reversible disulphide bond with another cysteine. The disulphide bond formation often triggers switches in protein structure and activity, especially when the distance between the two cysteine sulphur atoms is longer than the resulting disulphide bond distance. As an early example for the reversible disulphide bond-mediated functional switches, the reduced and oxidized forms of the bacterial transcription factor OxyR were characterized by X-ray crystallography. Recently, the Drosophila vision signalling protein, the association of inactivation-no-afterpotential D (INAD) was analysed by structural and functional methods. The two conserved cysteines of INAD were found to cycle between reduced and oxidized states during the light signal processing in Drosophila eyes, which was achieved by conformation dependent modulation of the disulphide bond redox potential. The production of the hypertension control peptide angiotensins was also shown to be controlled by the reversible disulphide bond in the precursor protein angiotensinogen. The crystal structure of the complex of angiotensiongen with its processing enzyme renin elucidated the role of the disulphide bond in stabilizing the precursor-enzyme complex facilitating the production of angiotensins. The increasing importance of the disulphide bond-mediated redox switches in normal and diseased states has implications in the development of novel antioxidant-based therapeutic approaches.</P>