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PDBsum entry 2z81
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Immune system
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PDB id
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2z81
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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 tlr1-Tlr2 heterodimer induced by binding of a tri-Acylated lipopeptide.
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Authors
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M.S.Jin,
S.E.Kim,
J.Y.Heo,
M.E.Lee,
H.M.Kim,
S.G.Paik,
H.Lee,
J.O.Lee.
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Ref.
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Cell, 2007,
130,
1071-1082.
[DOI no: ]
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PubMed id
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Abstract
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TLR2 in association with TLR1 or TLR6 plays an important role in the innate
immune response by recognizing microbial lipoproteins and lipopeptides. Here we
present the crystal structures of the human TLR1-TLR2-lipopeptide complex and of
the mouse TLR2-lipopeptide complex. Binding of the tri-acylated lipopeptide,
Pam(3)CSK(4), induced the formation of an "m" shaped heterodimer of
the TLR1 and TLR2 ectodomains whereas binding of the di-acylated lipopeptide,
Pam(2)CSK(4), did not. The three lipid chains of Pam(3)CSK(4) mediate the
heterodimerization of the receptor; the two ester-bound lipid chains are
inserted into a pocket in TLR2, while the amide-bound lipid chain is inserted
into a hydrophobic channel in TLR1. An extensive hydrogen-bonding network, as
well as hydrophobic interactions, between TLR1 and TLR2 further stabilize the
heterodimer. We propose that formation of the TLR1-TLR2 heterodimer brings the
intracellular TIR domains close to each other to promote dimerization and
initiate signaling.
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Figure 1.
Figure 1. Crystallized TLR-VLR Hybrid Proteins
Full-length and VLR hybrids of TLR1 (A) and TLR2 (B) are
represented schematically. TLR1 and TLR2 and hagfish VLRB.61 are
shown in green, blue, and white boxes, respectively. The
ligand-binding and dimerization domains were identified from our
crystal structure. Amino acid sequences at the fusion boundaries
and the corresponding conserved patterns are given underneath
the boxes. The sequences within the parentheses are non-native
sequences from the cloning sites.
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Figure 4.
Figure 4. The Lipopeptide-Binding Site of the Human TLR1-TLR2
Complex
(A) TLR1 and TLR2 residues involved in Pam[3]CSK[4]
binding are drawn in green and blue, respectively. The hydrogen
bonds are shown by broken red lines. Carbons, nitrogens,
oxygens, and a sulfur of the Pam[3]CSK[4] are colored in orange,
blue, red, and green, respectively. The H3 helix is drawn as a
coil for clarity. I319' of TLR1 is hidden behind the H3′
helix.
(B) Chemical structure of Pam[3]CSK[4.] Residues
interacting with Pam[3]CSK[4] are labeled. Hydrogen bonds are
drawn with broken red lines.
(C) The shape of the
Pam[3]CSK[4]-binding pocket is shown in mesh. Molecular surfaces
that belong to TLR1 and TLR2 are drawn in green and blue,
respectively. Pam[3]CSK[4] is shown as a space-filling model.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(2007,
130,
1071-1082)
copyright 2007.
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