1mik
From Proteopedia
THE ROLE OF WATER MOLECULES IN THE STRUCTURE-BASED DESIGN OF (5-HYDROXYNORVALINE)-2-CYCLOSPORIN: SYNTHESIS, BIOLOGICAL ACTIVITY, AND CRYSTALLOGRAPHIC ANALYSIS WITH CYCLOPHILIN A
Overview
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).
About this Structure
1MIK is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
The role of water molecules in the structure-based design of (5-hydroxynorvaline)-2-cyclosporin: synthesis, biological activity, and crystallographic analysis with cyclophilin A., Mikol V, Papageorgiou C, Borer X, J Med Chem. 1995 Aug 18;38(17):3361-7. PMID:7650689 Page seeded by OCA on Sat May 3 01:06:57 2008
