藥物Tranilast可阻絕S100A12蛋白與V-domain的結合

Blocking the interaction between S100A12 and the V domain of Receptor for Advanced Glycation End products (RAGE) by tranilast

邱建維(Chiou Jian-Wei)

指導教授 ： 余靖

國立清華大學/理學院/化學系/碩士(2016年)

摘要

摘要
人類S100A12蛋白質(或鈣粒蛋白C)是屬於S100家族蛋白質之一，此系列蛋白多為小分子蛋白且水溶液中多以雙聚體存在。當鈣離子與S100A12結合時，鈣離子會接上結構中EF-hand的部分，促使蛋白構型改變並活化蛋白，可與多種蛋白作用，產生生物反應。RAGE (Receptor for Advanced glycation end products)蛋白為一種免疫球蛋白，與生物體內發炎反應、糖尿病相關，是近年備受矚目的蛋白。RAGE可接收不同配體，其中S100家族蛋白大多與其有相互作用，而近幾年研究指出，S100A12與RAGE 的結合會造成細胞增生或發炎的症狀，與癌症或糖尿病息息相關。
Tranilast是一種已商業量產之抗過敏藥物，目前主要用於治療過敏相關症狀，而在本篇研究中，發現其對於S100A12蛋白與RAGE V domain蛋白間作用，能夠產生有效的抑制，被認定為可作為抑制劑的藥物。為探討其抑制的機制，本篇論文中，利用許多生物與物理上技術，像是核磁共振儀、螢光光譜儀、HADDOCK軟體以及WST-1 細胞實驗，來得到蛋白產生結合的相關結構資訊。
本篇論文中，我們分別探討了S100A12和tranilast以及S100A12和RAGE V domain的錯合物結構，其中發現了tranilast的結合位置能夠擋住S100A12與RAGE V domain的結合位置，這樣的現象能夠幫助新藥物的開發，發展能夠抑制RAGE和S100A12結合的藥物，藉以治療相關疾病。

關鍵字

S100A12 ； RAGE V domain ； 蛋白質作用 ； 蛋白質結構 ； Tranilast

並列摘要

Abstract
S100A12 (Calgranuline C) is a small and dimeric protein which belongs to the S100 family. When calcium ions bind to the two EF-hands of S100A12, the protein structure changes and promotes the interaction with its target proteins. RAGE (receptor for advanced glycation end) is one of the target protein for S100A12. By the past research, it showed the binding between these two proteins generated a pro-inflammatory response and activated several signal pathways such as ERK and NF-κB. It is an effective way that preventing the formation of S100A12-RAGE protein complex to inhibit various cancers.
Tranilast, an anti-allergic drug that is usually used as treatment of allergic disorders, was found to have a strong interaction with S100A12 which may be a potential inhibitor. In this study, we discussed the interaction of S100A12 with RAGE and S100A12 with tranilast by their three dimension structure. We utilized several biophysical techniques, including multidimensional NMR spectroscopy, fluorescence spectroscopy, HADDOCK and WST-1 assay to characterize the structural information of protein complex.
This study describes structural properties of S100A12-tranilast and S100A12-RAGE complex. It shows that tranilast blocks the binding sites of S100A12- RAGEV. This result can be useful for the development of new drug against various diseases.

並列關鍵字

S100A12 ； RAGE V domain ； Protein-Protein interaction ； Protein Structure ； Tranilast

參考文獻

Abstract

S100A12 (Calgranuline C) is a small and dimeric protein which belongs to the S100 family. When calcium ions bind to the two EF-hands of S100A12, the protein structure changes and promotes the interaction with its target proteins. RAGE (receptor for advanced glycation end) is one of the target protein for S100A12. By the past research, it showed the binding between these two proteins generated a pro-inflammatory response and activated several signal pathways such as ERK and NF-κB. It is an effective way that preventing the formation of S100A12-RAGE protein complex to inhibit various cancers.

Tranilast, an anti-allergic drug that is usually used as treatment of allergic disorders, was found to have a strong interaction with S100A12 which may be a potential inhibitor. In this study, we discussed the interaction of S100A12 with RAGE and S100A12 with tranilast by their three dimension structure. We utilized several biophysical techniques, including multidimensional NMR spectroscopy, fluorescence spectroscopy, HADDOCK and WST-1 assay to characterize the structural information of protein complex.

This study describes structural properties of S100A12-tranilast and S100A12-RAGE complex. It shows that tranilast blocks the binding sites of S100A12- RAGEV. This result can be useful for the development of new drug against various diseases.