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PDBsum entry 1dv8
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Signaling protein
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PDB id
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1dv8
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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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Crystal structure of the carbohydrate recognition domain of the h1 subunit of the asialoglycoprotein receptor.
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Authors
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M.Meier,
M.D.Bider,
V.N.Malashkevich,
M.Spiess,
P.Burkhard.
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Ref.
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J Mol Biol, 2000,
300,
857-865.
[DOI no: ]
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PubMed id
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Abstract
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The human asialoglycoprotein receptor (ASGPR), also called hepatic lectin, is an
integral membrane protein and is responsible for the clearance of desialylated,
galactose-terminal glycoproteins from the circulation by receptor-mediated
endocytosis. It can be subdivided into four functional domains: the cytosolic
domain, the transmembrane domain, the stalk and the carbohydrate recognition
domain (CRD). The galactose-binding domains belong to the superfamily of C-type
(calcium-dependent) lectins, in particular to the long-form subfamily with three
conserved intramolecular disulphide bonds. It is able to bind terminal
non-reducing galactose residues and N-acetyl-galactosamine residues of
desialated tri or tetra-antennary N-linked glycans. The ASGPR is a potential
liver-specific receptor for hepatitis B virus and Marburg virus and has been
used to target exogenous molecules specifically to hepatocytes for diagnostic
and therapeutic purposes.Here, we present the X-ray crystal structure of the
carbohydrate recognition domain of the major subunit H1 at 2.3 A resolution.
While the overall fold of this and other known C-type lectin structures are well
conserved, the positions of the bound calcium ions are not, indicating that the
fold is stabilised by alternative mechanisms in different branches of the C-type
lectin family. It is the first CRD structure where three calcium ions form an
intergral part of the structure. In addition, the structure provides direct
confirmation for the conversion of the ligand-binding site of the
mannose-binding protein to an asialoglycoprotein receptor-like specificity
suggested by Drickamer and colleagues. In agreement with the prediction that the
coiled-coil domain of the ASGPR is separated from the CRD and its N-terminal
disulphide bridge by several residues, these residues are indeed not
alpha-helical, while in tetranectin they form an alpha-helical coiled-coil.
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Figure 1.
Figure 1. Ribbon diagram of the H1-CRD. The two a-helices are shown in magenta, the b-strands in blue, the cal-
cium ions in green and the three disulphide bridges in yellow. Both the N and the C terminus are on the bottom of
the image. The division of the structure into two subdomains can be seen. Note the sharp bend in b-strand 3. The
sugar binds to calcium ion 2 in front of the glycine-rich loop in the upper part of the picture (marked by a black
arrow). All Figures were drawn using the program DINO (Philippsen, 1999: http://www.bioz.unibas.ch/~xray/
dino).
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Figure 3.
Figure 3. Overlay of the sugar-binding site of the H1-CRD of the ASGPR (grey) and the CRD of the QPDWGH
mutant of the MBP (brown) containing an N-acetyl galactosamine (NGA) molecule as ligand (green). An omit map of
the water molecules of the H1-CRD is shown contoured at a s-level of 3.5 (red).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2000,
300,
857-865)
copyright 2000.
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Secondary reference #1
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Title
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Mechanism of n-Acetylgalactosamine binding to a c-Type animal lectin carbohydrate-Recognition domain.
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Authors
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A.R.Kolatkar,
A.K.Leung,
R.Isecke,
R.Brossmer,
K.Drickamer,
W.I.Weis.
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Ref.
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J Biol Chem, 1998,
273,
19502-19508.
[DOI no: ]
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PubMed id
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Figure 4.
Fig. 4. Ribbon representation of crystal structure of the
QPDWGH mutant of MBP complexed with GalNAc. Stereo ribbon
drawing shows the vicinity of the GalNAc binding site with the
sugar and selected residues drawn as balls-and-sticks. The
glycine-rich loop stacked against Trp189 is highlighted in gray
and Ca^2+ 1 and 2 are shown as gray spheres. The hydrogen bond
between Ser154 and His202 is drawn as a dashed line.
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Figure 5.
Fig. 5. van der Waals dot surface representation of the
GalNAc binding site of the QPDWGH mutant of MBP. Stereo pair
shows the GalNAc binding site in an orientation very similar to
that in Fig. 4. The His202/GalNAc contact is apparent at the
bottom. The stacking of the glycine-rich loop, Trp189 ring, and
the apolar face of GalNAc is seen at the top. This figure was
prepared with the Xfit component of the XtalView program suite
(24).
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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