Molecular Cynamics Simulations of Bovine Cathepsin B and Its Complex with CA074

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概要

• 論文の詳細を見る

• To promote our better understanding of the dynamic stability of the bovine cathepsin B structure, which is characterized by an extra disulfide bond at Cys148-Cys252 from the other species, and of the binding stability of CA074 (a cathepsin B-specific inhibitor), molecular dynamics (MD) simulations were performed for the enzyme and its CA074 complex, assuming a system in aqueous solution at 300k. The MD simulation covering 400 ps indicated that the existence of a Cys148-Cys252 disulfide bond increases the conformational flexbility of the occluding loop, although the conformational stability of the overall structure is little affected. The structural characteristics of the complex elucidated by X-ray analysis were suggested to be also intrinsic and stable in the dynamic state; the hydrogen bonding/electrostatic interactions between the main and side chains of CA074 and the Sn and Sn' subsites of the enzyme were maintained throughout the MD simulation. Furthermore, the simulation made clear that the binding of CA074 singificantly restricted the conformational flexibility of the substrate binding region, especially the occluding loop, of cathepsin B. Statistical analyses during the simulation suggest that the selectivity of CA074 for cathepsin B stems from the tight P1'-S1' and P2'-S2' interactions, assisted in particular by double hydrogen bonds between the carboxyl two oxygens of the CA074 C-terminus and the imidazole NH groups of His110 and His111 residues.

• 公益社団法人日本薬学会の論文
• 2000-04-01

著者

• 石田 尚行

  電気通信大量子物質工

• 石田 尚之

  電通大電気通信学部

• 北村 和則

  富山化学工業株式会社綜合研究所

• ISHIDA Toshimasa

  Osaka University of Pharmaceutical Sciences

• YAMAMOTO Atsushi

  Department of Surgery, Hiroshima Prefectural Akitsu Hospital

• TOMOO Koji

  Department of Pyysical Chemistry, Osaka University of Pharmaceutical Sciences

• ISHIDA Toshimasa

  Department of Pyysical Chemistry, Osaka University of Pharmaceutical Sciences

• KITAMURA Kunihiro

  Research Center of Taisho Pharmaceutical Co., Ltd.

• Ishida Toshimasa

  Department Of Physical Chemistry Osaka University Of Pharmaceutical Sciences

• Kitamura Keisuke

  Kyoto Pharmaceutical University

• Koji Tomoo

  Department Of Physical Chemistry Osaka University Of Pharmaceutical Sciences

• Tomoo Koji

  Department Of Physical Chemistry Osaka University Of Pharmaceutical Sciences

• MIYAGAWA Hiroo

  Research Center, Taisho Pharmaceutical Co., Ltd.

• Iwashita T

  Suntory Institute For Bioorganic Research

• TAKAOKA Yuji

  Research Center, Taisho Pharmaceutical Co., Ltd.,

• SUMIYA Shigeyuki

  Research Center, Taisho Pharmaceutical Co., Ltd.,

• Takaoka Yuji

  Research Center Taisho Pharmaceutical Co. Ltd.

• Miyagawa H

  Research Center Taisho Pharmaceutical Co. Ltd.

• Ishida T

  Departments Of Biochemistry Shiga University Of Medical Science

• Yamamoto A

  Institute Of Bio-active Science Nippon Zoki Pharmaceutical Co. Ltd.

• Kitamura K

  Kyoto Pharmaceutical University

• 北村 和則

  Kyoto Pharmaceutical University

• Ishida Toshimasa

  Osaka Univ. Of Pharmaceutical Sciences

• Yamamoto Atsushi

  Department Of Biological Chemistry College Of Bioscience And Biotechnology Chubu University

• Shimabayashi S

  Research Center Taisho Pharmaceutical Co. Ltd.

• Yamamoto Atsushi

  Department of Applied Chemistry, Faculty of Engineering, Utsunomiya University

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