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PDBsum entry 2fyj
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Protein binding
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PDB id
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2fyj
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References listed in PDB file
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Key reference
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Title
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Binding site structure of one lrp-Rap complex: implications for a common ligand-Receptor binding motif.
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Authors
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G.A.Jensen,
O.M.Andersen,
A.M.Bonvin,
I.Bjerrum-Bohr,
M.Etzerodt,
H.C.Thøgersen,
C.O'Shea,
F.M.Poulsen,
B.B.Kragelund.
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Ref.
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J Mol Biol, 2006,
362,
700-716.
[DOI no: ]
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PubMed id
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Abstract
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The low-density lipoprotein receptor-related protein (LRP) interacts with more
than 30 ligands of different sizes and structures that can all be replaced by
the receptor-associated protein (RAP). The double module of complement type
repeats, CR56, of LRP binds many ligands including all three domains of RAP and
alpha2-macroglobulin, which promotes the catabolism of the Abeta-peptide
implicated in Alzheimer's disease. To understand the receptor-ligand cross-talk,
the NMR structure of CR56 has been solved and ligand binding experiments with
RAP domain 1 (RAPd1) have been performed. From chemical shift perturbations of
both binding partners upon complex formation, a HADDOCK model of the complex
between CR56 and RAPd1 has been obtained. The binding residues are similar to a
common binding motif suggested from alpha2-macroglobulin binding studies and
provide evidence for an understanding of their mutual cross-competition pattern.
The present structural results convey a simultaneous description of both binding
partners of an LRP-ligand complex and open a route to a broader understanding of
the binding specificity of the LRP receptor, which may involve a general
four-residue receptor-ligand recognition motif common to all LRP ligands. The
present result may be beneficial in the design of antagonists of ligand binding
to the LDL receptor family, and especially of drugs for treatment of Alzheimer's
disease.
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Figure 4.
Figure 4. HADDOCK program model of the complex between
RAPd1 and CR56 of LRP. (a) Backbone trace showing the three
α-helices of RAPd1 and the two CR modules of CR56 with
β-hairpins. (b) Hydrophobic interface with residues of Rapd1
and CR56 involved shown in van der Waals' surface representation
in yellow and orange, respectively, and residues named
accordingly. (c) The three networks of salt bridges between
residues of RAPd1 and CR56. Network I is located below the
hydrophobic cluster shown in (b) and network II at the rim of
the interface.
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Figure 7.
Figure 7. Suggested LRP recognition motif. (a) Schematic
representation of the four residues D/E-K-W-Ψ interaction
motif. Ψ is a hydrophobic residue or a residue with a
significant non-polar part. (b)–(d) Views of the identified
motifs in (b) LRP–RAP represented by the present HADDOCK model
for CR56–RAPd1, (c) the structure of VLDLR in complex with the
human rhinovirus (PDB accession code 1N7D) and (d) the low pH
structure of LDL with interactions between LB5 and the
β-propeller (PDB accession code 19VU).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2006,
362,
700-716)
copyright 2006.
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Secondary reference #1
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Title
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The solution structure of the n-Terminal domain of alpha2-Macroglobulin receptor-Associated protein.
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Authors
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P.R.Nielsen,
L.Ellgaard,
M.Etzerodt,
H.C.Thogersen,
F.M.Poulsen.
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Ref.
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Proc Natl Acad Sci U S A, 1997,
94,
7521-7525.
[DOI no: ]
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PubMed id
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Figure 3.
Fig. 3. (a) A stereo view of the backbone of RAPd1T
structure. Helix H1 is red, H2 is yellow, and H3 is green. The
unordered parts (see legend to Fig. 2) of the molecule are shown
as thin gray lines. (b) The water-accessible surface of the
RAPd1T structure. The color code is as in a. The arrow points to
the position of^ the groove that may be the structural component
involved in receptor binding. The figure has been prepared using
INSIGHT II (Biosym Technologies, San Diego).
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Figure 4.
Fig. 4. The interactions of Phe-20 (shown by spacefilling of
the side chain) with residues from H1 and H2 are shown. The red
(oxygen) and white (hydrogen) spacefillings mark the hydrogen
bonds between the side chain of Asn-26 and the backbone of
Phe-20. The figure^ has been prepared using Insight II (Biosym
Technologies).
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Secondary reference #2
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Title
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Identification of the minimal functional unit in the low density lipoprotein receptor-Related protein for binding the receptor-Associated protein (rap). A conserved acidic residue in the complement-Type repeats is important for recognition of rap.
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Authors
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O.M.Andersen,
L.L.Christensen,
P.A.Christensen,
E.S.Sørensen,
C.Jacobsen,
S.K.Moestrup,
M.Etzerodt,
H.C.Thogersen.
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Ref.
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J Biol Chem, 2000,
275,
21017-21024.
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PubMed id
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