Structural Basis for the Binding Mechanism of Human Serum Albumin Complexed with Cyclic Peptide Dalbavancin

Sho Ito, Akinobu Senoo, Satoru Nagatoishi, Masahito Ohue, Masaki Yamamoto, Kouhei Tsumoto, Naoki Wakui

研究成果: ジャーナルへの寄稿学術誌査読

13 被引用数 (Scopus)

抄録

Cyclic peptides, with unique structural features, have emerged as new candidates for drug discovery; their association with human serum albumin (HSA; long blood half-life) is crucial to improve drug delivery and avoid renal clearance. Here, we present the crystal structure of HSA complexed with dalbavancin, a clinically used cyclic peptide. Small-angle X-ray scattering and isothermal titration calorimetry experiments showed that the HSA-dalbavancin complex exists in a monomeric state; dalbavancin is only bound to the subdomain IA of HSA in solution. Structural analysis and MD simulation revealed that the swing of Phe70 and movement of the helix near dalbavancin were necessary for binding. The flip of Leu251 promoted the formation of the binding pocket with an induced-fit mechanism; moreover, the movement of the loop region including Glu60 increased the number of noncovalent interactions with HSA. These findings may support the development of new cyclic peptides for clinical use, particularly the elucidation of their binding mechanism to HSA.

本文言語英語
ページ(範囲)14045-14053
ページ数9
ジャーナルJournal of Medicinal Chemistry
63
22
DOI
出版ステータス出版済み - 11月 25 2020
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 分子医療
  • 創薬

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