Song J S, Park H, Hong H J, Yu M H, Ryu S E
Protein Engineering Research Division, Korea Research Institute of Bioscience & Biotechnology, KIST, Taejon, South Korea.
J Comput Aided Mol Des. 1998 Sep;12(5):419-24. doi: 10.1023/a:1008064228464.
Platelet production in blood is regulated by a lineage specific humoral factor, thrombopoietin (TPO). The amino terminal domain of TPO (TPO-N) is responsible for the signal transduction mediated by the TPO receptor, c-mpl. From the predicted length of helices we found that TPO-N belongs to the long-chain subfamily of the four-helix bundle cytokine family. We built a three dimensional model of TPO-N by a comparative homology modeling procedure. The four helices of TPO-N with an up-up-down-down topology are stabilized by a tightly packed central hydrophobic core and the extended loop AB makes an additional hydrophobic core with helices B and D outside of the four helix bundle scaffold. An interpretation of the previous site directed mutageneses results in light of the model enabled us to identify two isolated receptor binding sites. The surface made of Lys 136, Lys 138 and Lys 140 in helix D, and Pro 42 and Glu 50 in loop AB forms the first receptor binding site, while the surface of Asp 8, Arg 10 and Lys 14 in helix A represents the second binding site for the sequential receptor oligomerization.
血液中的血小板生成受一种谱系特异性体液因子——血小板生成素（TPO）调控。TPO的氨基末端结构域（TPO-N）负责由TPO受体c-mpl介导的信号转导。从预测的螺旋长度来看，我们发现TPO-N属于四螺旋束细胞因子家族的长链亚家族。我们通过比较同源建模方法构建了TPO-N的三维模型。TPO-N的四个螺旋呈上下上下拓扑结构，由紧密堆积的中央疏水核心稳定，延伸的环AB在四螺旋束支架之外与螺旋B和D形成额外的疏水核心。根据该模型对先前定点诱变结果的解释使我们能够识别出两个独立的受体结合位点。由螺旋D中的赖氨酸136、赖氨酸138和赖氨酸140以及环AB中的脯氨酸42和谷氨酸50形成的表面构成第一个受体结合位点，而螺旋A中的天冬氨酸8、精氨酸10和赖氨酸14的表面则代表第二个受体结合位点，用于连续的受体寡聚化。
