Isotope-edited NMR of cyclosporin A bound to cyclophilin: evidence for a trans 9,10 amide bond

doi:10.1126/science.2255910

Account Information

Guest Alerts | Access Rights | My Account | Sign In

Site Navigation

Article Views

Article Tools

My Science

Science 7 December 1990:
Vol. 250. no. 4986, pp. 1406 - 1409
DOI: 10.1126/science.2255910

Prev | Table of Contents | Next

Articles

Science, Vol 250, Issue 4986, 1406-1409
Copyright © 1990 by American Association for the Advancement of Science

articles

Isotope-edited NMR of cyclosporin A bound to cyclophilin: evidence for a trans 9,10 amide bond

SW Fesik, RT Gampe Jr, TF Holzman, DA Egan, R Edalji, Luly JR, R Simmer, R Helfrich, V Kishore, and DH Rich

Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, IL 60064.

The binding of a 13C-labeled cyclosporin A (CsA) analog to cyclophilin (peptidyl prolyl isomerase) was examined by means of isotope-edited nuclear magnetic resonance (NMR) techniques. A trans 9,10 peptide bond was adopted when CsA was bound to cyclophilin, in contrast to the cis 9,10 peptide bond found in the crystalline and solution conformations of CsA. Furthermore, nuclear Overhauser effects (NOEs) were observed between the zeta 3 and epsilon 3 protons of the methylleucine (MeLeu) residue at position 9 of CsA and tryptophan121 (Trp121) and phenylalanine (Phe) protons of cyclophilin, suggesting that the MeLeu9 residue of CsA interacts with cyclophilin. These results illustrate the power of isotope-edited NMR techniques for rapidly providing useful information about the conformations and active site environment of inhibitors bound to their target enzymes.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:

1H and 13C-NMR and Molecular Dynamics Studies of Cyclosporin A Interacting with Magnesium(II) or Cerium(III) in Acetonitrile. Conformational Changes and cis-trans Conversion of Peptide Bonds.: F. Bernardi, E. Gaggelli, E. Molteni, E. Porciatti, D. Valensin, and G. Valensin (2006)
Biophys. J. 90, 1350-1361
| Abstract » | Full Text » | PDF »

NMR Solution Structures of {delta}-Conotoxin EVIA from Conus ermineus That Selectively Acts on Vertebrate Neuronal Na+ Channels.: L. Volpon, H. Lamthanh, J. Barbier, N. Gilles, J. Molgo, A. Menez, and J.-M. Lancelin (2004)
J. Biol. Chem. 279, 21356-21366
| Abstract » | Full Text » | PDF »

Mutations That Perturb Cyclophilin A Ligand Binding Pocket Confer Cyclosporin A Resistance in Saccharomycescerevisiae.: M. E. Cardenas, E. Lim, and J. Heitman (1995)
J. Biol. Chem. 270, 20997-21002
| Abstract » | Full Text » | PDF »

Solution Structure of Taxol Determined Using a Novel Feedback-Scaling Procedure for Noe-Restrained Molecular Dynamics.: R. E. Cachau, R. Gussio, J. A. Beutler, G. N. Chmurny, B. D. Hilton, G. M. Muschik, and J. W. Erickson (1994)
International Journal of High Performance Computing Applications 8, 24-34
| Abstract » | PDF »