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  • 标题:Geometrical Conversion of the EGFR Extracellular Domain by Adiabatic Mapping Combining Normal Mode Analysis of the Elastic Network Model and Energy Optimization
  • 本地全文:下载
  • 作者:Hiroyuki Nojima ; Yasuomi Kiyota ; Genki Terashi
  • 期刊名称:Chemical and Pharmaceutical Bulletin
  • 印刷版ISSN:0009-2363
  • 电子版ISSN:1347-5223
  • 出版年度:2019
  • 卷号:67
  • 期号:10
  • 页码:1061-1071
  • DOI:10.1248/cpb.c19-00205
  • 出版社:The Pharmaceutical Society of Japan
  • 摘要:

    The activation of epidermal growth factor receptor (EGFR) involves the geometrical conversion of the extracellular domain (ECD) from the tethered to the extended forms with the dynamic rearrangement of the relative positions of four subdomains (SDs); however, this conversion process has not yet been thoroughly understood. We compare the two different forms of the X-ray crystal structures of ECD and simulate the ECD conversion process using adiabatic mapping that combines normal mode analysis of the elastic network model (ENM-NMA) and energy optimization. A comparison of the crystal structures reveals the rigidity of the intradomain geometry of the SD-I and -III backbone regardless of the form. The forward mapping from the tethered to the extended forms retains the intradomain geometry of the SD-I and -III backbone and reveals the trends to rearrange the relative positions of SD-I and -III and to dissociate the C-terminal tail of SD-IV from the hairpin loop in SD-II. The reverse mapping from the extended to the tethered forms complements the promotion of ECD conversion in the presence of epidermal growth factor (EGF).

  • 关键词:epidermal growth factor receptor;elastic network model;adiabatic mapping;normal mode analysis;crystal structure;extracellular domain
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