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PDBsum entry 1f5f
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Signaling protein
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PDB id
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1f5f
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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-Binding specificity of human sex hormone-Binding globulin is influenced by occupancy of a zinc-Binding site.
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Authors
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G.V.Avvakumov,
Y.A.Muller,
G.L.Hammond.
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Ref.
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J Biol Chem, 2000,
275,
25920-25925.
[DOI no: ]
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PubMed id
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Abstract
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One calcium-binding site (site I) and a second poorly defined metal-binding site
(site II) have been observed previously within the amino-terminal laminin G-like
domain (G domain) of human sex hormone-binding globulin (SHBG). By soaking
crystals of this structure in 2.5 mm ZnCl(2), site II and a new metal-binding
site (site III) were found to bind Zn(2+). Site II is located close to the
steroid-binding site, and Zn(2+) is coordinated by the side chains of His(83)
and His(136) and the carboxylate group of Asp(65). In this site, Zn(2+) prevents
Asp(65) from interacting with the steroid 17beta-hydroxy group and alters the
conformations of His(83) and His(136), as well as a disordered region over the
steroid-binding site. Site III is formed by the side chains of His(101) and the
carboxylate group of Asp(117), and the distance between them (2.7 A) is
increased to 3.7 A in the presence of Zn(2+). The affinity of SHBG for estradiol
is reduced in the presence of 0. 1-1 mm Zn(2+), whereas its affinity for
androgens is unchanged, and chemically-related metal ions (Cd(2+) and Hg(2+))
have similar but less pronounced effects. This is not observed when Zn(2+)
coordination at site II is modified by substituting Gln for His(136). An
alteration in the steroid-binding specificity of human SHBG by Zn(2+) occupancy
of site II may be relevant in male reproductive tissues where zinc
concentrations are very high.
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Figure 1.
Fig. 1. Metal-binding sites in the amino-terminal G
domain of SHBG. Of the 205 residues of SHBG crystallized,
residues 13-131 and 136-188 are visible in the electron density.
The steroid DHT is in a ball and stick representation, whereas
the calcium-binding site (site I) and the zinc-bindings sites
(sites II and III) are shown by white and black spheres,
respectively. The figure was prepared with the program MOLSCRIPT
(36).
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Figure 6.
Fig. 6. Proposed structural rearrangements in the
proximity of the steroid-binding site of human SHBG in the
presence (A) and absence (B) of Zn2+ in metal-binding site II.
The model of the unoccupied metal-binding site II (B) is based
on a subtraction of the unambiguous conformations observed for
Asp65 and His83 in the presence of zinc (A) from the alternative
conformations of these residues observed when metal-binding site
II was partially occupied (see Fig. 2B). Note that neither the
crystallographic analysis nor the hydrogen bonding network in
which Asn82 participates allow us to distinguish whether its
nitrogen or oxygen atom points toward the steroid 17  -hydroxy
group.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2000,
275,
25920-25925)
copyright 2000.
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Secondary reference #1
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Title
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Crystal structure of human sex hormone-Binding globulin: steroid transport by a laminin g-Like domain.
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Authors
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I.Grishkovskaya,
G.V.Avvakumov,
G.Sklenar,
D.Dales,
G.L.Hammond,
Y.A.Muller.
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Ref.
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EMBO J, 2000,
19,
504-512.
[DOI no: ]
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PubMed id
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Figure 2.
Figure 2 The G domain fold in SHBG. (A and B) Ribbon
representation of the N-terminal domain of SHBG in two
orthogonal orientations. The  -strands
of the two sheets forming a -sandwich
are coloured in yellow and blue, respectively. The steroid 5
 -DHT
is shown in a ball and stick representation. The segment
130–135, which is expected to loop over the steroid-binding
pocket, is disordered and not visible in the electron density.
The calcium ion is shown as a green dot (figures generated with
MOLSCRIPT and RASTER3D; Kraulis, 1991; Merritt and Murphy,
1994). (C) Topology diagram of the -strands.
Triangles pointing upwards denote -strands
pointing out of the paper plane. The conserved disulfide bond
between residues 164 and 188 is indicated as a dashed line.
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Figure 3.
Figure 3 (A) Ribbon representation of the human SHBG dimer
coloured according to the atomic displacement factors
(temperature factors) and model for the packing of the
C-terminal G domains (in grey). The displacement factors range
from 12 (dark blue) to 55 Å^2 (red). (B) Stereo
representation of the steroid-binding pocket in an orientation
identical to that in Figure 2B. All side chains that are in
contact with the steroid are displayed. (C) Chemical structure
and atom numbering in 5 -DHT.
In testosterone, a double bond is present between atoms C4 and
C5. In oestradiol, ring A is aromatic, C19 is missing and the
carbonyl oxygen at C3 is replaced by a hydroxyl group.
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The above figures are
reproduced from the cited reference
which is an Open Access publication published by Macmillan Publishers Ltd
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