Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 380, Issue 1, Pages 244-251Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.05.012
Keywords
thyroxine-binding globulin; corticosteroid-binding globulin; serpin; cortisol; allosteric mechanism
Categories
Funding
- Biotechnology and Biological Sciences Research Council Funding Source: Medline
- British Heart Foundation Funding Source: Medline
- Wellcome Trust [082961] Funding Source: Medline
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Corticosteroids are transported in the blood by a serpin, corticosteroid-binding globulin (CBG), and their normally equilibrated release can be further triggered by the cleavage of the reactive loop of CBG. We report here the crystal structures of cleaved human CBG (eCBG) at 1.8-angstrom resolution and its complex with cortisol at 2.3-angstrom resolution. As expected, on cleavage, CBG undergoes the irreversible S-to-R serpin transition, with the cleaved reactive loops being fully incorporated into the central beta-sheet. A connecting loop of helix D, which is in a helix-like conformation in native CBG, unwinds and grossly perturbs the hormone binding site following beta-sheet expansion in the cCBG structure but shifts away from the binding site by more than 8 angstrom following the binding of cortisol. Unexpectedly, on cortisol binding, the hormone binding site of cCBG adopts a configuration almost identical with that of the native conformer. We conclude that CBG has adapted an allosteric mechanism of the serpins to allow equilibrated release of the hormones by a flip-flop movement of the intact reactive loop into and out of the beta-sheet. The change in the hormone binding affinity results from a change in the flexibility or plasticity of the connecting loop, which modulates the configuration of the binding site. (C) 2008 Elsevier Ltd. All rights reserved.
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