Homology modeling of the receptor binding domainof human thrombopoietin

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• 作者：Song ; Jin Soo ; Park ; Heungrok ; Hong ; Hyo Jeong ; Yu ; Myeong Hee ; Ryu ; Seong Eon
• 关键词：comparative modeling ; cytokine ; four ; helix bundle ; platelet ; receptor ; ligand interaction
• 刊名：Journal of Computer-Aided Molecular Design
• 出版年：1998
• 出版时间：1998
• 年：1998
• 卷：12
• 期：5
• 页码：419-424
• 全文大小：99 KB
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Physical Chemistry
  Computer Applications in Chemistry
  Animal Anatomy, Morphology and Histology
  
• 出版者：Springer Netherlands
• ISSN：1573-4951

文摘

Platelet production in blood is regulated by alineage specific humoral factor, thrombopoietin (TPO).The amino terminal domain of TPO (TPO-N) isresponsible for the signal transduction mediated bythe TPO receptor, c-mpl. From the predicted length ofhelices we found that TPO-N belongs to the long-chainsubfamily of the four-helix bundle cytokine family.We built a three dimensional model of TPO-N by acomparative homology modeling procedure. The fourhelices of TPO-N with an up-up-down-down topology arestabilized by a tightly packed central hydrophobiccore and the extended loop AB makes an additionalhydrophobic core with helices B and D outside of thefour helix bundle scaffold. An interpretation of theprevious site directed mutageneses results in light ofthe model enabled us to identify two isolated receptorbinding sites. The surface made of Lys 136, Lys 138and Lys 140 in helix D, and Pro 42 and Glu 50 in loopAB forms the first receptor binding site, while thesurface of Asp 8, Arg 10 and Lys14 in helix Arepresents the second binding site for the sequentialreceptor oligomerization.