Sanglifehrin A (SFA) is a recently discovered immunosuppressant
drug that shares its intracellular target with the
major immunosuppressant drug cyclosporin A (CsA). Both bind
to and inhibit the cyclophilins,a diverse family of proteins found
throughout nature that share a conserved catalytic domain.
Although they share this common protein target,the mechanism
of action of the cyclophilin^SFA complex has been reported as
distinct from that of the well-studied cyclophilin^CsA complex.
The X-ray structure of a macrolide analogue of SFA’s cyclic
region complexed with cyclophilin A has recently been resolved,
but this left the placement of the linear region of SFA unresolved.
Using ¢ve cyclophilins from the ¢ssion yeast Schizosaccharomyces
pombe,and a mutant of one of these proteins,
SpCyp3-F128W,we have shown that the sensitivity of cyclophilins
to SFA can be correlated to the same speci¢c tryptophan
residue that has previously been identi¢ed to correlate to CsA
sensitivity,and that the tail of SFA may be responsible for
mediating this sensitivity.
- 2003 Published by Elsevier B.V. on behalf of the Federation
of European Biochemical Societies