Characterization of novel non-peptide thrombopoietin mimetics, their species specificity and the activation mechanism of the thrombopoietin receptor

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• 作者：Noriko Yamane ; Yoshikazu Tanaka ; Naoki Ohyabu ; Shoji Yamane ; Kazuhiko Maekawa ; Jun Ishizaki ; Ryuji Suzuki ; Tsunetoshi Itoh ; Hiroshi Takemoto
• 关键词：Thrombopoietin ; Human thrombopoietin mimetics ; Species specificity ; Chimera/mutant receptor ; Loss/gain of function ; Megakaryocytosis
• 刊名：European Journal of Pharmacology
• 出版年：2008
• 出版时间：31 May 2008
• 年：2008
• 卷：586
• 期：1-3
• 页码：44-51
• 全文大小：849 K

文摘

A series of non-peptide small compounds discovered to be thrombopoietin receptor agonists showed species specificity to humans. Compound I could induce megakaryocyte lineage from human bone marrow cells, but not from mouse, guinea pig or cynomolgus monkey bone marrow cells. To elucidate the mechanism, we identified the pivotal amino acid residue for the receptor activation by compound I by taking advantage of its species specificity. The response of compound I to three human/mouse chimeric receptors indicated the importance of the transmembrane domain. Comparison of amino acid sequences of the transmembrane domain of the thrombopoietin receptor between human and three animal species led us to hypothesize that histidine 499 is necessary for the reactivity to the thrombopoietin mimetics. We verified the hypothesis using two mutant receptors: the human thrombopoietin receptor mutant His499Leu and the mouse thrombopoietin receptor mutant Leu490His. These results should be helpful for structure–activity relationship studies and conducting in vivo studies of thrombopoietin mimetics.