 |
PDBsum entry 2v6d
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transport protein
|
PDB id
|
|
|
|
2v6d
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Corticosteroid-Binding globulin, A structural basis for steroid transport and proteinase-Triggered release.
|
|
|
Authors
|
|
M.A.Klieber,
C.Underhill,
G.L.Hammond,
Y.A.Muller.
|
|
|
Ref.
|
|
J Biol Chem, 2007,
282,
29594-29603.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
94%.
|
|
|
|
Abstract
|
|
|
Corticosteroid-binding globulin (CBG) is a serine proteinase inhibitor (serpin)
family member that transports glucocorticoids in blood and regulates their
access to target cells. The 1.9A crystal structure of rat CBG shows that its
steroid-binding site resembles the thyroxin-binding site in the related serpin,
thyroxin-binding globulin, and mutagenesis studies have confirmed the
contributions of key residues that constitute the steroid-binding pocket. Unlike
thyroxin-bound thyroxin-binding globulin, the cortisol-bound CBG displays an
"active" serpin conformation with the proteinase-sensitive, reactive
center loop (RCL) fully expelled from the regulatory beta-sheet A. Moreover, the
CBG structure allows us to predict that complete insertion of the
proteolytically cleaved RCL into the serpin fold occurs in concert with a
displacement and unwinding of helix D that would disrupt the steroid-binding
site. This allosteric coupling between RCL positioning and occupancy of the CBG
steroid-binding site, which resembles the ligand (glycosamino-glycan)-dependent
activation of the thrombin inhibitory serpins heparin cofactor II and
anti-thrombin RCLs, ensures both optimal recognition of CBG by target
proteinases and efficient release of steroid to sites of action.
|
|
|
|
|
|
|
|
Figure 1.
FIGURE 1. Crystal structure of rat CBG. A and B, ribbon
representation of rat CBG viewed from two different angles.
Secondary structure elements are named according to the common
serpin nomenclature. The  -sheets A, B, and C are
colored in red, green, and blue, respectively. The trace of the
residues of the RCL not visible in electron density maps
(residues 329-338) is modeled by a dashed line. The steroid
(cortisol) is bound on top of sheet B and shown in yellow. C,
close-up of cortisol in the steroid-binding site. D,
representative portion of the final  [A]-weighted 2F[o] -
F[c] electron density map contoured at 1.0 and showing cortisol
with the surrounding residues Arg^10 and Trp^362.
|
|
Figure 3.
FIGURE 3. Hormone binding to CBG. A, stereo representation
of the CBG (blue) steroid-binding site. B, schematic depiction
of the interactions between CBG and cortisol. Water molecules
are shown as red dots, hydrophobic interactions are shown with
dashed lines, and polar interactions are shown with dotted lines
in A and B. C, for comparison, thyroxin-binding site in TBG
(Protein Data Bank code 2ceo). Note that similar residues are
involved in binding cortisol in CBG and thyroxin in TBG. D,
mapping of three different serpin ligand-binding sites onto the
CBG surface (in blue). Cortisol is shown in yellow, and thyroxin
is in green, as bound to TBG. Heparin (in orange) binds on top
of helix D in antithrombin (Protein Data Bank code 1e03) close
to the shared ligand-binding site in TBG and CBG.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
29594-29603)
copyright 2007.
|
|
|
|
|
|
|
