1MIK

THE ROLE OF WATER MOLECULES IN THE STRUCTURE-BASED DESIGN OF (5-HYDROXYNORVALINE)-2-CYCLOSPORIN: SYNTHESIS, BIOLOGICAL ACTIVITY, AND CRYSTALLOGRAPHIC ANALYSIS WITH CYCLOPHILIN A

1MIK の概要

• エントリーDOI: 10.2210/pdb1mik/pdb
• 関連するPDBエントリー: 1BCK 1C5F 1CSA 1CWA 1CWB 1CWC 1CWF 1CWH 1CWI 1CWJ 1CWK 1CWL 1CWM 1CWO 1CYA 1CYB 1CYN 1IKF 1M63 1MF8 1QNG 1QNH 1XQ7 2ESL 2OJU 2POY 2RMA 2RMB 2RMC 2WFJ 2X2C 2X7K 2Z6W 3BO7 3CYS 3EOV
• 関連するBIRD辞書のPRD_ID: PRD_000766
• 分子名称: PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A, CYCLOSPORIN A (3 entities in total)
• 機能のキーワード: isomerase-immunosuppressant complex, cyclophilin-cyclosporin complex, cyclosporin a, immunosuppressant, cyclophilin, isomerase/immunosuppressant
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 19287.16

構造登録者

Mikol, V. (登録日: 1995-09-20, 公開日: 1996-03-08, 最終更新日: 2024-06-05)

主引用文献

Mikol, V.,Papageorgiou, C.,Borer, X.
The Role of Water Molecules in the Structure-Based Design of (5-Hydroxynorvaline)-2-Cyclosporin: Synthesis, Biological Activity, and Crystallographic Analysis with Cyclophilin A.
J.Med.Chem., 38:3361-, 1995

PubMed Abstract: Analysis of the contact surface of the cyclophilin A (CypA)/cyclosporin A (CsA, 1) crystal structure delineates a unique cavity between both molecules in the vicinity of the Abu-2 side chain atoms of 1 (Abu pocket). Therefore, (5-hydroxynorvaline)-2-cyclosporin (2) was designed and prepared as a CsA derivative which could mediate additional interactions within the pocket. The X-ray crystal structure of the CypA/2 complex at 1.76 A resolution shows that 1 and 2 have identical backbone conformations and that the introduced hydroxypropyl chain makes indeed the expected supplemental interactions with CypA. However, 2 has 8-9-fold lower binding affinity than 1 for CypA. This results from a presumed unfavorable free energy change associated with the displacement of one of the tightly bound water molecules within the pocket and a change in prebinding equilibria. The role of the later was assessed by comparing the conformation distribution of 1 and 2 to that of norvaline-2-cyclosporin (3) and norvaline-2-(D-MeSer)-3-cyclosporin (4).

PubMed: 7650689
DOI: 10.1021/JM00017A020

実験手法

X-RAY DIFFRACTION (1.76 Å)