Cell：败血症的发病机理
韩国科学家日前宣布，他们已经破译了诱发败血症的肌体防御机制。
据韩联社报道，以韩国高等科学技术院的化学家李知昊（音译）为首的研究小组称，他们已绘制出会导致血中毒的ＴＬＲ１和ＴＬＲ２两种受体的基因图，研究结果发表在最新一期的《细胞》月刊上。
这个研究小组还于本月稍早时候公布了一项类似的突破性发现，他们绘制出了小鼠ＴＬＲ４（ＴＬＲ４－ＭＤ－２）受体的结构图。ＴＬＲ４－ＭＤ－２受体是另一种诱发败血症的蛋白质。
李知昊说：“了解ＴＬＲ１和ＴＬＲ２基因的形成以及人体的反应可以加快目前寻找治疗方法的速度。”全球科学家一直将ＴＬＲ４和ＴＬＲ２细胞视为找到败血症治疗方法的关键。
李知昊说，ＴＬＲ４细胞对感染人体的革兰氏阴性菌有反应，不过ＴＬＲ２则引发人体对革兰氏阳性菌形成自然免疫。他说，和发现ＴＬＲ４－ＭＤ－２的过程一样，科学家们使用了“混合ＬＲＲ技术”，即用某些蛋白质得到ＴＬＲ１和ＴＬＲ２的基因图。人们期待这一最新发现可以加快开发新一代疗效更好的败血症药物。
败血症俗称血中毒，死亡率在２０％到４０％之间。当人体自然免疫系统对细菌和病毒感染“反应过度”时，就会导致败血症。这种反应会诱发致命性肺衰竭、心衰、肝衰竭、肾衰竭以及败血症休克。（新华网）
原始出处:
Cell, Vol 130, 1071-1082, 21 September 2007
Article
Crystal Structure of the TLR1-TLR2 Heterodimer Induced by Binding of a Tri-Acylated Lipopeptide
Mi Sun Jin,1 Sung Eun Kim,1,4 Jin Young Heo,1,4 Mi Eun Lee,1 Ho Min Kim,1 Sang-Gi Paik,3 Hayyoung Lee,3 and Jie-Oh Lee1,2,
1 Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, Korea 305-701
2 Institute for Bio-Century, Korea Advanced Institute of Science and Technology, Daejon, Korea 305-701
3 Department of Biology, School of Bioscience & Biotechnology, Chungnam National University, Daejon, Korea 305-764
Corresponding author
Jie-Oh Lee
jieoh.lee@kaist.ac.kr
TLR2 in association with TLR1 or TLR6 plays an important role in the innate immune response by recognizing microbial lipoproteins and lipopeptides. Here we present the crystal structures of the human TLR1-TLR2-lipopeptide complex and of the mouse TLR2-lipopeptide complex. Binding of the tri-acylated lipopeptide, Pam3CSK4, induced the formation of an “m” shaped heterodimer of the TLR1 and TLR2 ectodomains whereas binding of the di-acylated lipopeptide, Pam2CSK4, did not. The three lipid chains of Pam3CSK4 mediate the heterodimerization of the receptor; the two ester-bound lipid chains are inserted into a pocket in TLR2, while the amide-bound lipid chain is inserted into a hydrophobic channel in TLR1. An extensive hydrogen-bonding network, as well as hydrophobic interactions, between TLR1 and TLR2 further stabilize the heterodimer. We propose that formation of the TLR1-TLR2 heterodimer brings the intracellular TIR domains close to each other to promote dimerization and initiate signaling.
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