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PDBsum entry 1d2s
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Transport protein
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PDB id
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1d2s
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Contents |
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* Residue conservation analysis
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DOI no:
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EMBO J
19:504-512
(2000)
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PubMed id:
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Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain.
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I.Grishkovskaya,
G.V.Avvakumov,
G.Sklenar,
D.Dales,
G.L.Hammond,
Y.A.Muller.
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ABSTRACT
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Human sex hormone-binding globulin (SHBG) transports sex steroids in blood and
regulates their access to target tissues. In biological fluids, SHBG exists as a
homodimer and each monomer comprises two laminin G-like domains (G domains). The
crystal structure of the N-terminal G domain of SHBG in complex with
5alpha-dihydrotestosterone at 1.55 A resolution reveals both the architecture of
the steroid-binding site and the quaternary structure of the dimer. We also show
that G domains have jellyroll topology and are structurally related to
pentraxin. In each SHBG monomer, the steroid intercalates into a hydrophobic
pocket within the beta-sheet sandwich. The steroid and a 20 A distant calcium
ion are not located at the dimer interface. Instead, two separate
steroid-binding pockets and calcium-binding sites exist per dimer. The structure
displays intriguing disorder for loop segment Pro130-Arg135. In all other
jellyroll proteins, this loop is well ordered. If modelled accordingly, it
covers the steroid-binding site and could thereby regulate access of ligands to
the binding pocket.
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Selected figure(s)
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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
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2000,
19,
504-512)
copyright 2000.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.M.Nakhla,
D.J.Hryb,
W.Rosner,
N.A.Romas,
Z.Xiang,
and
S.M.Kahn
(2009).
Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing.
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BMC Mol Biol,
10,
37.
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K.Chen,
and
L.Kurgan
(2009).
Investigation of atomic level patterns in protein--small ligand interactions.
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PLoS ONE,
4,
e4473.
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M.J.Heeb,
D.Prashun,
J.H.Griffin,
and
B.N.Bouma
(2009).
Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor.
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FASEB J,
23,
2244-2253.
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C.Reissner,
M.Klose,
R.Fairless,
and
M.Missler
(2008).
Mutational analysis of the neurexin/neuroligin complex reveals essential and regulatory components.
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Proc Natl Acad Sci U S A,
105,
15124-15129.
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G.Michels,
and
U.C.Hoppe
(2008).
Rapid actions of androgens.
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Front Neuroendocrinol,
29,
182-198.
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A.M.Hosie,
M.E.Wilkins,
and
T.G.Smart
(2007).
Neurosteroid binding sites on GABA(A) receptors.
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Pharmacol Ther,
116,
7.
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D.R.Gustafson,
C.Karlsson,
I.Skoog,
L.Rosengren,
L.Lissner,
and
K.Blennow
(2007).
Mid-life adiposity factors relate to blood-brain barrier integrity in late life.
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J Intern Med,
262,
643-650.
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V.M.Leppänen,
H.Tossavainen,
P.Permi,
L.Lehtiö,
G.Rönnholm,
A.Goldman,
I.Kilpelaïnen,
and
T.Pihlajamaa
(2007).
Crystal structure of the N-terminal NC4 domain of collagen IX, a zinc binding member of the laminin-neurexin-sex hormone binding globulin (LNS) domain family.
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J Biol Chem,
282,
23219-23230.
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PDB code:
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A.M.Hosie,
M.E.Wilkins,
H.M.da Silva,
and
T.G.Smart
(2006).
Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites.
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Nature,
444,
486-489.
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E.R.Graf,
Y.Kang,
A.M.Hauner,
and
A.M.Craig
(2006).
Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain.
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J Neurosci,
26,
4256-4265.
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K.E.Persson,
J.Stenflo,
S.Linse,
Y.Stenberg,
R.J.Preston,
D.A.Lane,
and
S.M.Rezende
(2006).
Binding of calcium to anticoagulant protein S: role of the fourth EGF module.
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Biochemistry,
45,
10682-10689.
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K.M.Ng,
M.G.Catalano,
T.Pinós,
D.M.Selva,
G.V.Avvakumov,
F.Munell,
and
G.L.Hammond
(2006).
Evidence that fibulin family members contribute to the steroid-dependent extravascular sequestration of sex hormone-binding globulin.
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J Biol Chem,
281,
15853-15861.
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L.R.Sheckler,
L.Henry,
S.Sugita,
T.C.Südhof,
and
G.Rudenko
(2006).
Crystal structure of the second LNS/LG domain from neurexin 1alpha: Ca2+ binding and the effects of alternative splicing.
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J Biol Chem,
281,
22896-22905.
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PDB code:
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P.Scotton,
D.Bleckmann,
M.Stebler,
F.Sciandra,
A.Brancaccio,
T.Meier,
J.Stetefeld,
and
M.A.Ruegg
(2006).
Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin.
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J Biol Chem,
281,
36835-36845.
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A.Fallahi,
B.Kroll,
L.R.Warner,
R.J.Oxford,
K.M.Irwin,
L.M.Mercer,
S.E.Shadle,
and
J.T.Oxford
(2005).
Structural model of the amino propeptide of collagen XI alpha1 chain with similarity to the LNS domains.
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Protein Sci,
14,
1526-1537.
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J.Stetefeld,
and
M.A.Ruegg
(2005).
Structural and functional diversity generated by alternative mRNA splicing.
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Trends Biochem Sci,
30,
515-521.
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A.W.Norman,
M.T.Mizwicki,
and
D.P.Norman
(2004).
Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model.
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Nat Rev Drug Discov,
3,
27-41.
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J.Stetefeld,
A.T.Alexandrescu,
M.W.Maciejewski,
M.Jenny,
K.Rathgeb-Szabo,
T.Schulthess,
R.Landwehr,
S.Frank,
M.A.Ruegg,
and
R.A.Kammerer
(2004).
Modulation of agrin function by alternative splicing and Ca2+ binding.
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Structure,
12,
503-515.
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PDB codes:
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B.Saposnik,
D.Borgel,
M.Aiach,
and
S.Gandrille
(2003).
Functional properties of the sex-hormone-binding globulin (SHBG)-like domain of the anticoagulant protein S.
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Eur J Biochem,
270,
545-555.
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J.Koepke,
E.I.Scharff,
C.Lücke,
H.Rüterjans,
and
G.Fritzsch
(2003).
Statistical analysis of crystallographic data obtained from squid ganglion DFPase at 0.85 A resolution.
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Acta Crystallogr D Biol Crystallogr,
59,
1744-1754.
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PDB code:
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J.Metzger,
A.Schnitzbauer,
M.Meyer,
M.Söder,
C.Y.Cuilleron,
H.Hauptmann,
E.Huber,
and
P.B.Luppa
(2003).
Binding analysis of 1alpha- and 17alpha-dihydrotestosterone derivatives to homodimeric sex hormone-binding globulin.
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Biochemistry,
42,
13735-13745.
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M.T.Mizwicki,
and
A.W.Norman
(2003).
Two key proteins of the vitamin D endocrine system come into crystal clear focus: comparison of the X-ray structures of the nuclear receptor for 1alpha,25(OH)2 vitamin D3, the plasma vitamin D binding protein, and their ligands.
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J Bone Miner Res,
18,
795-806.
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M.T.Overgaard,
E.S.Sorensen,
D.Stachowiak,
H.B.Boldt,
L.Kristensen,
L.Sottrup-Jensen,
and
C.Oxvig
(2003).
Complex of pregnancy-associated plasma protein-A and the proform of eosinophil major basic protein. Disulfide structure and carbohydrate attachment.
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J Biol Chem,
278,
2106-2117.
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Y.Kariya,
Y.Tsubota,
T.Hirosaki,
H.Mizushima,
W.Puzon-McLaughlin,
Y.Takada,
and
K.Miyazaki
(2003).
Differential regulation of cellular adhesion and migration by recombinant laminin-5 forms with partial deletion or mutation within the G3 domain of alpha3 chain.
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J Cell Biochem,
88,
506-520.
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G.V.Avvakumov,
I.Grishkovskaya,
Y.A.Muller,
and
G.L.Hammond
(2002).
Crystal structure of human sex hormone-binding globulin in complex with 2-methoxyestradiol reveals the molecular basis for high affinity interactions with C-2 derivatives of estradiol.
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J Biol Chem,
277,
45219-45225.
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PDB code:
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I.Grishkovskaya,
G.V.Avvakumov,
G.L.Hammond,
M.G.Catalano,
and
Y.A.Muller
(2002).
Steroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformation.
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J Biol Chem,
277,
32086-32093.
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PDB codes:
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K.N.Hogeveen,
P.Cousin,
M.Pugeat,
D.Dewailly,
B.Soudan,
and
G.L.Hammond
(2002).
Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction.
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J Clin Invest,
109,
973-981.
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T.K.Giri,
S.Linse,
P.García de Frutos,
T.Yamazaki,
B.O.Villoutreix,
and
B.Dahlbäck
(2002).
Structural requirements of anticoagulant protein S for its binding to the complement regulator C4b-binding protein.
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J Biol Chem,
277,
15099-15106.
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T.Sasaki,
P.G.Knyazev,
Y.Cheburkin,
W.Göhring,
D.Tisi,
A.Ullrich,
R.Timpl,
and
E.Hohenester
(2002).
Crystal structure of a C-terminal fragment of growth arrest-specific protein Gas6. Receptor tyrosine kinase activation by laminin G-like domains.
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J Biol Chem,
277,
44164-44170.
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PDB code:
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A.S.Wong,
W.Y.Lui,
I.T.Hui,
and
W.M.Lee
(2001).
Rabbit sex hormone-binding globulin: expression in the liver and testis during postnatal development and structural characterization by truncated proteins.
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Int J Androl,
24,
165-174.
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B.O.Villoutreix,
B.Dahlbäck,
D.Borgel,
S.Gandrille,
and
Y.A.Muller
(2001).
Three-dimensional model of the SHBG-like region of anticoagulant protein S: new structure-function insights.
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Proteins,
43,
203-216.
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G.Rudenko,
E.Hohenester,
and
Y.A.Muller
(2001).
LG/LNS domains: multiple functions -- one business end?
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Trends Biochem Sci,
26,
363-368.
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P.H.Petra,
E.T.Adman,
W.R.Orr,
K.T.Woodcock,
C.Groff,
and
L.M.Sui
(2001).
Arginine-140 and isoleucine-141 determine the 17beta-estradiol-binding specificity of the sex-steroid-binding protein (SBP, or SHBG) of human plasma.
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Protein Sci,
10,
1811-1821.
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S.Sugita,
F.Saito,
J.Tang,
J.Satz,
K.Campbell,
and
T.C.Südhof
(2001).
A stoichiometric complex of neurexins and dystroglycan in brain.
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J Cell Biol,
154,
435-445.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
