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

Fesik SW, Gampe RT, Holzman TF, Egan DA, Edalji R, Luly JR, Simmer R, Helfrich R, Kishore V, Rich DH
Science. 1990 250 (4986): 1406-9

PMID: 2255910 · DOI:10.1126/science.2255910

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.

MeSH Terms (15)

Amides Amino Acid Isomerases Carbon Isotopes Carrier Proteins Cyclosporins Escherichia coli Humans Leucine Magnetic Resonance Spectroscopy Peptidylprolyl Isomerase Phenylalanine Protein Binding Protein Conformation Recombinant Proteins Tryptophan

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