Two crystal structures of the FK506-binding domain of Plasmodium falciparum FKBP35 in complex with rapamycin at high resolution
Citation:
Bianchin A, Allemand F, Bell A, Chubb A.J, Guichou J.-F, Two crystal structures of the FK506-binding domain of Plasmodium falciparum FKBP35 in complex with rapamycin at high resolution, Acta Crystallographica Section D: Biological Crystallography, 71, 2015, 1319 - 1327Download Item:
Bianchin et al Acta Cryst D preprint.pdf (Published (author's copy) - Peer Reviewed) 6.391Mb
Abstract:
Antimalarial chemotherapy continues to be challenging in view of the emergence of drug resistance,
especially artemisinin resistance in Southeast Asia. It is critical that we identify novel anti-malarial drugs
that inhibit new targets with unexplored mechanisms of action. It has been demonstrated that the
immunosuppressive drug rapamycin, currently in clinical use to prevent organ transplant rejection, has
anti-malarial effects. The Plasmodium falciparum target protein is PfFKBP35, a unique immunophilin
FK506 binding protein (FKBP). This protein family binds rapamycin, FK506 and other immunosuppressive
and non-immunosuppressive macrolactones.
Here we report two crystallographic structures of rapamycin in complex with the FK506-binding domain of
PfFKBP35 at high resolution, in both its oxidised and reduced forms. Comparison to the human FKBP12-
rapamycin complex reported earlier, the structures reveal structural differences in the 4-6 segment that
lines the rapamycin binding site. Structural differences between the Plasmodium protein and the human
hFKBP12 include the replacement of Cys-106 and Ser-109 by His-87 and Ile-90, respectively. Cys-106 which
is close (4-5 Å) from atoms of rapamycin, suggests possible routes for the rational design of analogues of
rapamycin with specific antiparasitic activity. Comparison of the structures with the PfFKBD-FK506
complex shows that both drugs interact with the same binding site residues. These two new structures
highlight the structural differences and the specific interactions that must be kept in consideration for the
rational design of rapamycin analogues with anti-malarial activity that specifically bind to PfFKBP35
without immunosuppressive effect
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Author: BELL, ANGUS
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Acta Crystallographica Section D: Biological Crystallography71
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