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Targeting allosteric sites for protein tyrosine phosphatase inhibition
류성언,김승준 한국구조생물학회 2014 Biodesign Vol.2 No.3
Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of phosphorylated protein substrates during cellsignaling processes. Although various PTPs have been implicated as drug targets for human diseases, there have beenno examples of therapeutics that target PTPs. Conventionally, PTP inhibitor developments mainly targeted the activesite pocket whose structural characteristics limited the discovery of optimal compounds with potency, selectivity andmembrane permeability. Recent approaches for allosteric inhibition have shed light on the development of therapeuticsthat 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 regionsgenerated by the opening of the flexible D-loop were identified as allosteric inhibition sites. In PTP1B, the C-terminaldisordered regions were found to bind novel non-competitive inhibitors. The novel inhibitors targeting those allosteric sitesshowed remarkable target-selectivity, potency, and in vivo activity. Approaches for allosteric inhibition provide excitingopportunities for the development of new PTP-targeting therapeutics for the effective treatment of cancer, diabetes,immune disorders and central nervous system diseases.
B . stearothermophilus 의 내열성 α - amylase 의 클로닝과 대장균 , 고초균에서의 발현
류성언,정현순,양철학 ( Seong Eon Ryu,Hyun Soon Chung,Chul Hak Yang ) 생화학분자생물학회 1985 BMB Reports Vol.18 No.4
The gene coding for thermostable extracellular α-amylase of thermophilic bacteria, Bacillus stearothermophilus was cloned and expressed both in E. coli and B. subtilis. By transforming E. coli HB101 with PBR322 containing chromosomal DNA fragments of B. stearothermophilus which was digested with EcoRI, colonies that showed α-amylase activity was obtained. The plasmids from those colonies contained a 4,200 by insert at the EcoRI site of pBR322. After transformed the 4,200 by fragment to pMK4 which is a shuttle vector between E. coli and B. subtilis, we transformed B. subtilis with these resulting hybrid plasmid. We present evidence that the cloned fragment codes for a B. stearothermophilus α-amylase which is heat stable. The foreign gene was expressed efficiently both in E. coli and B. subtilis and was maintained stably.
Structure and Design of Broadly-Neutralizing Antibodies Against HIV
류성언,Wayne A. Hendrickson 한국분자세포생물학회 2012 Molecules and cells Vol.34 No.3
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 immunolo-gical 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.
Symposium 2 : Free Radical and Oxidative Stress ; Protein Switches in the Cellular Redox Regulation
류성언 ( Lyu Seong Eon ) 한국지질동맥경화학회 ( 구 한국지질학회 ) 2002 韓國脂質學會誌 Vol.12 No.3
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 studi
Structure of the Catalytic Domain of Protein Tyrosine Phosphatase Sigma in the Sulfenic Acid Form
전태진,류성언,치엔,전하정 한국분자세포생물학회 2013 Molecules and cells Vol.36 No.1
Protein tyrosine phosphatase sigma (PTP) plays a vital role in neural development. The extracellular domain of PTP binds to various proteoglycans, which control the activity of 2 intracellular PTP domains (D1 and D2). To understand the regulatory mechanism of PTP, we carried out structural and biochemical analyses of PTP D1D2. In the crystal structure analysis of a mutant form of D1D2 of PTP, we unexpectedly found that the catalytic cysteine of D1 is oxidized to cysteine sulfenic acid, while that of D2 remained in its reduced form, sug-gesting that D1 is more sensitive to oxidation than D2. This finding contrasts previous observations on PTP. The cysteine sulfenic acid of D1 was further confirmed by immunoblot and mass spectrometric analyses. The stabilization of the cysteine sulfenic acid in the active site of PTP suggests that the formation of cysteine sulfenic acid may function as a stable intermediate during the redox-regulation of PTPs.