Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation

Yunn, Na-Oh,Koh, Ara,Han, Seungmin,Lim, Jong Hun,Park, Sehoon,Lee, Jiyoun,Kim, Eui,Jang, Sung Key,Berggren, Per-Olof,Ryu, Sung Ho Oxford University Press 2015 Nucleic acids research Vol.43 No.16

<P>Due to their high affinity and specificity, aptamers have been widely used as effective inhibitors in clinical applications. However, the ability to activate protein function through aptamer-protein interaction has not been well-elucidated. To investigate their potential as target-specific agonists, we used SELEX to generate aptamers to the insulin receptor (IR) and identified an agonistic aptamer named IR-A48 that specifically binds to IR, but not to IGF-1 receptor. Despite its capacity to stimulate IR autophosphorylation, similar to insulin, we found that IR-A48 not only binds to an allosteric site distinct from the insulin binding site, but also preferentially induces Y1150 phosphorylation in the IR kinase domain. Moreover, Y1150-biased phosphorylation induced by IR-A48 selectively activates specific signaling pathways downstream of IR. In contrast to insulin-mediated activation of IR, IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells. Instead, AKT S473 phosphorylation is highly stimulated by IR-A48, resulting in increased glucose uptake both <I>in vitro</I> and <I>in vivo</I>. Here, we present IR-A48 as a biased agonist able to selectively induce the metabolic activity of IR through allosteric binding. Furthermore, our study also suggests that aptamers can be a promising tool for developing artificial biased agonists to targeted receptors.</P>

A stepwise activation model for the insulin receptor

Yunn Na-Oh,Kim Junhong,Ryu Sung Ho,Cho Yunje 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

The binding of insulin to the insulin receptor (IR) triggers a cascade of receptor conformational changes and autophosphorylation, leading to the activation of metabolic and mitogenic pathways. Recent advances in the structural and functional analyses of IR have revealed the conformations of the extracellular domains of the IR in inactive and fully activated states. However, the early activation mechanisms of this receptor remain poorly understood. The structures of partially activated IR in complex with aptamers provide clues for understanding the initial activation mechanism. In this review, we discuss the structural and functional features of IR complexed with various ligands and propose a model to explain the sequential activation mechanism. Moreover, we discuss the structures of IR complexed with biased agonists that selectively activate metabolic pathways and provide insights into the design of selective agonists and their clinical implications.

Mechanistic understanding of insulin receptor modulation: Implications for the development of anti-diabetic drugs

Yunn, Na-Oh,Kim, Jaeyoon,Kim, Youndong,Leibiger, Ingo,Berggren, Per-Olof,Ryu, Sung Ho Elsevier 2018 Pharmacology & therapeutics Vol.185 No.-

<P><B>Abstract</B></P> <P>The insulin receptor is an important regulator of metabolic processes in the body, and in particular of glucose homeostasis, including glucose uptake into peripheral tissues. Thus, insulin administration is an effective treatment for diabetes, which is characterized by chronic elevation of blood glucose. However, insulin is not only a metabolic regulator, but also functions as a growth hormone. Accordingly, studies of long-term insulin administration and of the hyperinsulinemia associated with type 2 diabetes have raised concerns about possible increases in the risks of cancer and atherosclerosis, due to excessive stimulation of cell proliferation. Interestingly, some insulin receptor ligands that have been developed based on a peptide, an antibody, and an aptamer selectively have metabolic effects exerted through the insulin receptor but do not cause significant cellular proliferation. Although these ligands therefore have potential as anti-diabetic drugs for advanced diabetes care, the mechanism whereby they specifically activate the insulin receptor is still unclear. Recently, studies of the structure of the insulin receptor have progressed considerably, and have provided further mechanistic understanding of insulin receptor activation. Based on this progress, we propose a mechanistic model of this specificity and discuss the potential for the development of novel anti-diabetic drugs that would not have the adverse effects caused by excessive mitogenic action.</P>

An aptamer agonist of the insulin receptor acts as a positive or negative allosteric modulator, depending on its concentration

Yunn Na-Oh,Lee Jimin,Lee Hye Sun,Oh Eun Ju,Park Mangeun,Park Seongeun,진서연,Shin Euisu,Lee Jo woon yi,Kim Youndong,배순식,Ryu Sung Ho 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Aptamers are widely used as binders that interact with targets with high affinity or as inhibitors of the function of target molecules. However, they have also been used to modulate target protein function, which they achieve by activating the target or stabilizing its conformation. Here, we report a unique aptamer modulator of the insulin receptor (IR), IR-A62. Alone, IR-A62 acts as a biased agonist that preferentially induces Y1150 monophosphorylation of IR. However, when administered alongside insulin, IR-A62 shows variable binding cooperativity depending on the ligand concentration. At low concentrations, IR-A62 acts as a positive allosteric modulator (PAM) agonist that enhances insulin binding, but at high concentrations, it acts as a negative allosteric modulator (NAM) agonist that competes with insulin for IR. Moreover, the concentration of insulin affects the binding of IR-A62 to IR. Finally, the subcutaneous administration of IR-A62 to diabetic mice reduces blood glucose levels with a longer-lasting effect than insulin administration. These findings imply that aptamers can elicit various responses from receptors beyond those of a simple agonist or inhibitor. We expect further studies of IR-A62 to help reveal the mechanism of IR activation and greatly expand the range of therapeutic applications of aptamers.

Study of Oil-Water Ratio and Flow Rate of MQL Fluid in High Speed Milling of Inconel 718

Yunn-Shiuan Liao,Chin-Hsi Liao,Hsien-Mou Lin 한국정밀공학회 2017 International Journal of Precision Engineering and Vol.18 No.2

High speed milling of Inconel 718 by carbide tool aided by MQL of various oil-water ratios and flow rates of the fluid was investigated. Tool wear and cutting force were taken to assess the effectiveness of the fluids. The action of the fluid in machining Inconel 718 under MQL was also studied. EDX analysis of the rake face of the tool shows that the fluid has penetrated into the chiptool interface and works as the diffusion barrier as well. The results reveal that the amounts of fluid penetration and wetting area are essential for effective fluid action. Tool wear and cutting force are found to decrease with increasing flow rate of the fluid irrespective of oil-water ratio. But the improvements are negligible as compared with those resulted from the flow rates of 100 ml/ hr and 60 ml/hr. This can also be confirmed by the little difference of wetting area beyond the flow rate of 60 ml/hr. Based on this study, it is concluded that the most appropriate oil-water ratio and flow rate of the fluid used in MQL in high speed milling of Inconel 718 are 60:40 and 60 ml/hr, respectively.

세계 인류무형문화유산의 홍보를 위한 디자인 연구: 한국의 인류무형문화유산을 중심으로

권윤경 ( Yunn Kyoung Kwon ) 한국기초조형학회 2014 기초조형학연구 Vol.15 No.2

현재 무형문화유산 정책과 활동 현황은 기본적으로 건축물, 사적, 기념물 등 주로 외형의 보존관리에 초점을 맞추고 있기 때문에 스토리텔링이 가능한 삶, 문화, 역사, 생활양식, 전통 등 무형적 가치가 등한시되어 왔다. 최근 유네스코는 무형문화유산보호협약을 제정하면서 유산의 무형적 가치를 중시하여 living heritage라는 개념이 강조되고 아울러 유산적 가치를 지속가능한 발전으로 연계시키는 노력을 하고 있지만 여전히 세계유산사업은 유산의 외형적 유지를 중시하고 있다. 본 연구목적은 한국 고유의 무형 문화유산이 가지고 있는 역사성이나 전통적 아름다움과 같은 정신적 가치 속성을 제대로 표현하고, 통일되어 있지 않은 한국의 세계인류무형문화유산 아이덴티티디자인을 하나의 공통된 방향 안에서 정립함으로서 통합적인 이미지를 구축하는데 있다. 2012년 12월 현재, 15건의 우리나라 인류무형문화유산의 시각이미지를 조사 분석하여, 효율적이고 직관적인 ``한국의 인류무형문화유산`` 포털 사이트 개설과 각 유산들의 상징에 대한 컨셉디자인을 제안, 향후 통합된 이미지 구축을 통해 우리나라의 세계인류무형문화유산에 대한 인식과 홍보를 보다 효과적으로 할 수 있도록 하였다. Current Status of the Intangible Cultural Heritage policy is mainly focuses on the appearance of the conservation in building activities, historical sites, monuments, etc., intangible value such as life in which storytelling is possible, culture, history, lifestyle, tradition has been neglected. Recently, UNESCO enacted the Convention for the Safeguarding of Intangible Cultural Heritage emphasizing on ``living heritage`` which is stressing the intangible value of the heritage as well as making an effort to link heritage value to sustainable development, but the world heritage businesses are still emphasizing the outward of the heritage. Purpose of this study is to represent the spiritual values well which the Intangible Cultural Heritage of Korea has, such as historicity and the traditional beauty and to establish the unified image of Korea`s intangible cultural heritage by trying to classify the identity design in one common direction. I did research on fifteen visual images of the Korean intangible cultural heritage in December 2012 at present, proposed to open the efficient and intuitive ``Korean intangible cultural heritage of humanity`` portal site and suggested the concept design about the symbol of the each heritage. Thus, want to help promote recognition and PR for world intangible cultural heritage of humanity more effectively through the establishment of integrated image.

Utilization of Big Data Analytics to Personalize Online Brand Experiences : A Case Study of A Popular Online Shopping Brand in South Korea

Wun Yunn, Chìn 한국브랜드디자인학회 2018 한국브랜드디자인학회 학술대회 Vol.2018 No.-

The Role of UX and UI Design as a Branding Strategy for E-commerce Success in South Korea.

Wun Yunn, Chin 한국브랜드디자인학회 2017 한국브랜드디자인학회 학술대회 Vol.2017 No.-

DACUM 기법을 활용한 금연상담사의 직무분석

김윤희(Kim Yunn hee),강승희(Kang Seung hee),김현숙(Kim Hyun sook),강정찬(Kang Jung chan),이상주(Lee Sang ju) 학습자중심교과교육학회 2017 학습자중심교과교육연구 Vol.17 No.1

본 연구는 DACUM 기법을 사용하여 금연상담사의 직무를 분석하여 금연상담사의 직무를 구성하는 책무와 과업을 추출하였으며, 과업별 중요도, 난이도, 빈도를 밝히고 직무분석 내용을 구조화하였다. DACUM 직무분석을 위하여 8명의 SME, 1명의 촉진자, 3명의 관찰자와 2명의 서기로 이루어진 DACUM 직무위원회를 구성하였으며 도출된 직무모델을 검증하기 위해 설문조사를 실시하였다. 직무분석의 결과 흡연 및 금연에 대하여 이해하기, 금연상담 실시하기, 행동요법 수행하기, 약물요법 수행하기, 금연상담기법 적용하기, 흡연예방 및 금연교육 실시하기, 흡연예방 및 금연사업 홍보하기, 대상자 관리하기, 행정 업무하기, 전문적 역량 강화하기의 10개의 직무영역과 38개의 과업이 추출되었다. 본 연구에서 추출된 책무와 과업에 대해 금연상담 관련 시설 및 기관에 근무하고 있는 163명을 대상으로 2015년 8월 6일부터 2015년 8월 21일까지 직무분석 모델에 대한 중요도와 난이도, 빈도 등에 대한 요구분석을 실시하였고, 각 과업에 대한 중요지수 및 우선순위를 파악하였다. 또한 본 연구에서 추출된 책무와 과업에 대한 중요도, 난이도, 수행빈도에 대해 금연상담사 경력에 따라 차이가 있는지를 분석하였다. 이러한 연구의 결과는 금연상담사의 전문직무역량 향상을 위한 교육과정 개발의 기초자료로 활용될 수 있을 것이다. The purpose of this study was to analyze smoking cessation counselors jobs using the DACUM method. In according to DACUM basic principles, DACUM workshops were held by the DACUM committee participated in a panel of eight SMEs(Subject Matter Expert) and three education experts. This research extracts the 10 duties and 38 tasks of smoking cessation counselors jobs. and suggest a job model for smoking cessation counselors by examining each task s importance, difficulties, frequency. To verify the job model of smoking cessation counselors , the survey were carried out targeting managers and practitioners with qualifications of smoking cessation counselors with questionnaire composed of ten duties and thirty eight tasks of job model. Also the duty was defined by the DACUM procedures, then statistical methods were conducted through the verification process to test the importance, difficulty, frequency, and order of priority of ten duties and thirty-eight tasks in job model. It is expected that the results of this paper will be used as foundational material to improve smoking cessation counselors specialized job skills and also to develop the curriculum for them.

에너지함수에 의한 통합안정도해석

문영현(Young-Yunn Moon),이응혁(Eung-Hyuk Lee),이윤섭(Yoon-Seop Lee),오용택(Yong-Taeg Oh),김백(Baik Kim) 대한전기학회 1996 대한전기학회 학술대회 논문집 Vol.1996 No.11