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PDBsum entry 1lhu
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Transport protein
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PDB id
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1lhu
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Steroid ligands bind human sex hormone-Binding globulin in specific orientations and produce distinct changes in protein conformation.
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Authors
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I.Grishkovskaya,
G.V.Avvakumov,
G.L.Hammond,
M.G.Catalano,
Y.A.Muller.
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Ref.
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J Biol Chem, 2002,
277,
32086-32093.
[DOI no: ]
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PubMed id
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Abstract
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The amino-terminal laminin G-like domain of human sex hormone-binding globulin
(SHBG) contains a single high affinity steroid-binding site. Crystal structures
of this domain in complex with several different steroid ligands have revealed
that estradiol occupies the SHBG steroid-binding site in an opposite orientation
when compared with 5 alpha-dihydrotestosterone or C19 androgen metabolites (5
alpha-androstan-3 beta,17 beta-diol and 5 alpha-androstan-3 beta,17 alpha-diol)
or the synthetic progestin levonorgestrel. Substitution of specific residues
within the SHBG steroid-binding site confirmed that Ser(42) plays a key role in
determining high affinity interactions by hydrogen bonding to functional groups
at C3 of the androstanediols and levonorgestrel and the hydroxyl at C17 of
estradiol. Among residues participating in the hydrogen bond network with
hydroxy groups at C17 of C19 steroids or C3 of estradiol, Asp(65) appears to be
the most important. The different binding mode of estradiol is associated with a
difference in the position/orientation of residues (Leu(131) and Lys(134)) in
the loop segment (Leu(131)-His(136)) that covers the steroid-binding site as
well as others (Leu(171)-Lys(173) and Trp(84)) on the surface of human SHBG and
may provide a basis for ligand-dependent interactions between SHBG and other
macromolecules. These new crystal structures have also enabled us to construct a
simple space-filling model that can be used to predict the characteristics of
novel SHBG ligands.
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Figure 2.
Fig. 2. Stereo images of the human SHBG steroid-binding
site occupied by 3  ,17 Adiol (A), 3
,17  Adiol (B),
and levonorgestrel (C). The orientation of these ligands within
the human SHBG steroid-binding site is similar to that observed
previously for DHT (8). Images were prepared with Molscript (34)
and Raster3d (35).
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Figure 3.
Fig. 3. Estradiol binds to human SHBG in an opposite
orientation when compared with 3 ,17 Adiol. A,
stereo image of the human SHBG steroid-binding site occupied by
estradiol. B, superposition of the steroid-binding site in the 3
,17 Adiol (in
blue) and estradiol (in yellow) complexes, illustrating the
differences in steroid orientation and coordination. Images were
prepared with Molscript (34) and Raster3d (35).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2002,
277,
32086-32093)
copyright 2002.
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