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Figure 14.1
The structures of natural product immunophilin ligands.
non-immunosuppressive (Figure 14.1). Anity methods were used to identify
putative protein-binding partners,
15,16
named FK-506 binding proteins
(FKBPs), a subfamily of the immunophilins exemplified by the 12 kDa
FKBP12. FKBPs possess peptidyl-prolyl cis-trans isomerase (PPIase) activ-
ities
17
and are known to form complexes with ion channels,
18-20
steroid
receptor complexes,
21
transcription factors,
22
tubulin,
23
and B-cell CLL/lym-
phoma 2 (Bcl-2) upon conditional activation.
24
It soon became apparent that
binding to FKBP12 did not on its own account for rapamycin's antifungal and
immunosuppressive activities, but rather that they arose from the formation of
a high anity ternary complex between the rapamycin-FKBP12 complex and
what was then a new protein of unknown function named target of rapamycin
(TOR) in yeast.
25
The highly conserved mammalian homolog of TOR (mTOR, also called
FRAP, RAFT, and SEP), a large molecular weight (4250 kDa) member of the
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