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Science 12 July 1996:
Vol. 273. no. 5272, pp. 239 - 242
DOI: 10.1126/science.273.5272.239
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Reports

Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP

Jungwon Choi, * Jie Chen, Stuart L. Schreiber, Jon Clardy dagger

Rapamycin, a potent immunosuppressive agent, binds two proteins: the FK506-binding protein (FKBP12) and the FKBP-rapamycin-associated protein (FRAP). A crystal structure of the ternary complex of human FKBP12, rapamycin, and the FKBP12-rapamycin-binding (FRB) domain of human FRAP at a resolution of 2.7 angstroms revealed the two proteins bound together as a result of the ability of rapamycin to occupy two different hydrophobic binding pockets simultaneously. The structure shows extensive interactions between rapamycin and both proteins, but fewer interactions between the proteins. The structure of the FRB domain of FRAP clarifies both rapamycin-independent and -dependent effects observed for mutants of FRAP and its homologs in the family of proteins related to the ataxia-telangiectasia mutant gene product, and it illustrates how a small cell-permeable molecule can mediate protein dimerization.

J. Choi and J. Clardy, Department of Chemistry, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA.
J. Chen and S. L. Schreiber, Howard Hughes Medical Institute and Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
* Present address: Department of Chemistry, Suwon University, Kyunggi 445-773, South Korea.
dagger To whom correspondence should be addressed.


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Science. ISSN 0036-8075 (print), 1095-9203 (online)