PDBsum entry 2vdy

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Transport protein PDB id
Protein chain
361 a.a. *
HCY ×2
Waters ×165
* Residue conservation analysis
PDB id:
Name: Transport protein
Title: Crystal structure of the reactive loop cleaved corticosteroid binding globulin complexed with cortisol
Structure: Corticosteroid-binding globulin. Chain: a, b. Fragment: residues 33-405. Synonym: cbg, transcortin, serpin a6, human corticosteroid- globulin. Engineered: yes. Mutation: yes. Other_details: complexed with cortisol
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli,.
2.30Å     R-factor:   0.213     R-free:   0.271
Authors: A.Zhou,Z.Wei,R.J.Read
Key ref:
A.Zhou et al. (2008). The S-to-R transition of corticosteroid-binding globulin and the mechanism of hormone release. J Mol Biol, 380, 244-251. PubMed id: 18513745 DOI: 10.1016/j.jmb.2008.05.012
13-Oct-07     Release date:   13-May-08    
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Protein chains
No UniProt id for this chain
Struc: 361 a.a.
Key:    Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   1 term 


DOI no: 10.1016/j.jmb.2008.05.012 J Mol Biol 380:244-251 (2008)
PubMed id: 18513745  
The S-to-R transition of corticosteroid-binding globulin and the mechanism of hormone release.
A.Zhou, Z.Wei, P.L.Stanley, R.J.Read, P.E.Stein, R.W.Carrell.
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 (cCBG) at 1.8-A resolution and its complex with cortisol at 2.3-A 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 A 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.
  Selected figure(s)  
Figure 1.
Fig. 1. Structures of CBG and TBG. (a) Native rat CBG–cortisol complex structure^6 has a closed five-stranded A-sheet (red) with the connecting loop (green) on top of helix D in a helical conformation. (b) TBG–thyroxine complex has a partially opened A-sheet with the reactive loop (yellow) partially inserted. Missing residues of the reactive loop in the structures are shown as dashed lines, and the protease cleavage site is arrowed. The structures of cCBG (d) and its complex with cortisol (c) show that the reactive loop (yellow) is fully incorporated in the central β-sheet with helix D partially unwound. The changes in helix D of CBG mirror similar changes in antithrombin: the connecting loop adopts a two-turn helical conformation when heparin is bound (e) but unwinds due to steric hindrance when the reactive loop is partially inserted into the A-sheet (f). Helix H is in cyan and helix A is in blue in (a)–(d), whereas helix D in E and F is in light blue. Cortisol and thyroxine are shown in spheres. For clarity, helix F of antithrombin is not shown.
Figure 3.
Fig. 3. Mechanism of hormone binding and release. Serpins are known to be able to form a series of conformers with a range of reactive loop (RCL, in red) and A-sheet configurations. Insertion of the reactive loop and the opening of the A-sheet are linked to other flexible regions of the serpin molecule, including the binding sites for heparin (hD) and vitronectin,^17 while the resulting changes in flexibility or plasticity of hD (in green), as shown here, directly affect the hormone binding site. The structures of cCBG, together with other results discussed here, indicate a dynamic sequence, with native CBG having a limited sheet entry as in frame I with a four-residues-shorter reactive loop compared with TBG and antithrombin, and high binding affinity. The conformation of native TBG is represented in frame II with an intermediate affinity for thyroxine but equilibrates towards frame I with higher affinity when the reactive loop is shortened by three residues or towards frame III with low affinity when the loop is extended by three residues.^[18]^ and ^[19] Protease cleavage of the reactive loop results in its incorporation into the central β-sheet A to form, typically irreversibly, a stable relaxed conformation (frame IV).
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 380, 244-251) copyright 2008.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21371536 D.E.Henley, and S.L.Lightman (2011).
New insights into corticosteroid-binding globulin and glucocorticoid delivery.
  Neuroscience, 180, 1-8.  
19245336 B.Gooptu, and D.A.Lomas (2009).
Conformational pathology of the serpins: themes, variations, and therapeutic strategies.
  Annu Rev Biochem, 78, 147-176.  
19011238 H.Y.Lin, C.Underhill, B.R.Gardill, Y.A.Muller, and G.L.Hammond (2009).
Residues in the Human Corticosteroid-binding Globulin Reactive Center Loop That Influence Steroid Binding before and after Elastase Cleavage.
  J Biol Chem, 284, 884-896.  
19528533 Z.Wei, Y.Yan, R.W.Carrell, and A.Zhou (2009).
Crystal structure of protein Z-dependent inhibitor complex shows how protein Z functions as a cofactor in the membrane inhibition of factor X.
  Blood, 114, 3662-3667.
PDB code: 3f1s
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