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PDBsum entry 3hi6
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Cell adhesion/immune system
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PDB id
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3hi6
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Contents |
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180 a.a.
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213 a.a.
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210 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural basis of activation-Dependent binding of ligand-Mimetic antibody al-57 to integrin lfa-1.
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Authors
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H.Zhang,
J.H.Liu,
W.Yang,
T.Springer,
M.Shimaoka,
J.H.Wang.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
18345-18350.
[DOI no: ]
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PubMed id
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Abstract
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The activity of integrin LFA-1 (alpha(L)beta(2)) to its ligand ICAM-1 is
regulated through the conformational changes of its ligand-binding domain, the I
domain of alpha(L) chain, from an inactive, low-affinity closed form (LA), to an
intermediate-affinity form (IA), and then finally, to a high-affinity open form
(HA). A ligand-mimetic human monoclonal antibody AL-57 (activated LFA-1 clone
57) was identified by phage display to specifically recognize the
affinity-upregulated I domain. Here, we describe the crystal structures of the
Fab fragment of AL-57 in complex with IA, as well as in its unligated form. We
discuss the structural features conferring AL-57's strong selectivity for the
high affinity, open conformation of the I domain. The AL-57-binding site
overlaps the ICAM-1 binding site on the I domain. Furthermore, an antibody Asp
mimics an ICAM Glu by forming a coordination to the metal-ion dependent adhesion
site (MIDAS). The structure also reveals better shape complementarity and a more
hydrophobic interacting interface in AL-57 binding than in ICAM-1 binding. The
results explain AL-57's antagonistic mimicry of LFA-1's natural ligands, the
ICAM molecules.
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Figure 2.
MIDAS of the I domain in different conformations. The MIDAS
residues of the I domain are shown as stick models and colored
with purple carbon atoms in IA in the AL-57/IA structure (A),
green carbon atoms in HA in the ICAM-3/HA structure (B, PDB code
1T0P) and cyan carbon atoms in the unligated IA with closed
conformation (C, PDB code 1MJN). Acidic residues from ligands
D101 in AL-57 (A) and E37 in ICAM-3 (B), are also shown as stick
models with yellow carbon atoms. All oxygen atoms are in red.
Metal ions in the MIDAS are labeled and shown as spheres. Waters
in MIDAS are shown as red spheres and labeled with a “w.”
Coordination bonds are shown as dashed lines. Compared to the
closed conformation in the unligated IA, in which D239
coordinated to the MIDAS metal ion directly (C), D239 in IA(A)
or HA (B) coordinated to the metal ion via a water molecule and
the metal ion shifted about 2.3Å and coordinated to T206
directly.
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Figure 3.
(A) Interacting residues in the binding interface. Aromatic
residues from AL-57, which contribute a significant level of
hydrophobic interaction, are shown as stick models with yellow
carbons. E241 from IA and R31(H) from AL-57, which form
electrostatic interactions, are also shown as stick models with
yellow carbons. The metal ion in MIDAS is shown as a purple
sphere. D101(H) from AL-57 is shown as a stick model in yellow.
(B) The movement of the C-terminal α7 helix in IA. The
wild-type LA (PDB code 3F74), unligated IA (PDB code 1MJN), IA
in the AL-57/IA complex, and HA in the ICAM-3/HA (PDB code 1T0P)
complex, were superimposed and colored in gold, cyan, magenta,
and green, respectively. For clarity, only the α1 helices, β6
strands, β6-α7 loops, and α7 helices are shown as Cα traces.
The engineered disulfide bonds (Cys-161-Cys-299 in IA and
Cys-287-Cys-294 in HA) are shown as stick models. Compared to
unligated IA, the β6-α7 loop of IA in AL-57/IA complex moved
downward like that observed in HA, indicating an open
conformation.
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