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PDBsum entry 2yx8
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Protein transport
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PDB id
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2yx8
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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 human receptor activity-Modifying protein 1 extracellular domain.
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Authors
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S.Kusano,
M.Kukimoto-Niino,
R.Akasaka,
M.Toyama,
T.Terada,
M.Shirouzu,
T.Shindo,
S.Yokoyama.
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Ref.
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Protein Sci, 2008,
17,
1907-1914.
[DOI no: ]
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PubMed id
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Abstract
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Receptor activity-modifying protein (RAMP) 1 forms a heterodimer with calcitonin
receptor-like receptor (CRLR) and regulates its transport to the cell surface.
The CRLR.RAMP1 heterodimer functions as a specific receptor for calcitonin
gene-related peptide (CGRP). Here, we report the crystal structure of the human
RAMP1 extracellular domain. The RAMP1 structure is a three-helix bundle that is
stabilized by three disulfide bonds. The RAMP1 residues important for
cell-surface expression of the CRLR.RAMP1 heterodimer are clustered to form a
hydrophobic patch on the molecular surface. The hydrophobic patch is located
near the tryptophan residue essential for binding of the CGRP antagonist,
BIBN4096BS. These results suggest that the hydrophobic patch participates in the
interaction with CRLR and the formation of the ligand-binding pocket when it
forms the CRLR.RAMP1 heterodimer.
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Figure 3.
Structural features of the molecular surface of RAMP1. (A)
Ribbon representation of RAMP1. The two views are related by a
180[deg] rotation about the vertical axis. The three disulfide
bonds are shown in yellow. (B) Blue and red surfaces represent
positive and negative potentials, respectively. The molecular
orientations in B, C, and D are the same as in A. The circle
indicates the location of the hydrophobic patch, which exists in
the shallow concave area between [alpha]2 and [alpha]3. (C)
Residue conservation mapping on the surface of RAMP1. Red and
orange surfaces indicate the locations of identical and similar
residues among human RAMPs, respectively, according to the
sequence alignment in Figure 1A Figure 1.- .
(D) Mapping of the binding-site residues on the RAMP1 surface.
Residues Phe93, His97, Tyr101, which are reportedly important
for the formation of the RAMP1[center dot]CRLR interaction
(Kuwasako et al. 2001, 2003; Simms et al. 2006), are colored
pink. Trp74, which was previously identified as the
high-affinity binding site of the nonpeptide antagonist
BIBN4096BS (Doods et al. 2000; Mallee et al. 2002), is colored
cyan. Leu94, which when replaced by alanine reportedly caused a
great increase in cell-surface expression and CRLR binding, is
colored yellow.
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Figure 4.
View of the putative RAMP1 interface region with CRLR.
Selected residues in Figure 3D Figure 3.- are
labeled. Note that among the residues that are reportedly
important for the formation of the RAMP1[center dot]CRLR
interface (pink), the side chains of Phe93 and Tyr101 point
toward the inside of the molecule, while that of His97 points
toward the outside the molecule.
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(2008,
17,
1907-1914)
copyright 2008.
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