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PDBsum entry 2sdf
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References listed in PDB file
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Key reference
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Title
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Solution structure and basis for functional activity of stromal cell-Derived factor-1; dissociation of cxcr4 activation from binding and inhibition of HIV-1.
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Authors
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M.P.Crump,
J.H.Gong,
P.Loetscher,
K.Rajarathnam,
A.Amara,
F.Arenzana-Seisdedos,
J.L.Virelizier,
M.Baggiolini,
B.D.Sykes,
I.Clark-Lewis.
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Ref.
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Embo J, 1997,
16,
6996-7007.
[DOI no: ]
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PubMed id
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Abstract
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The three-dimensional structure of stromal cell-derived factor-1 (SDF-1) was
determined by NMR spectroscopy. SDF-1 is a monomer with a disordered N-terminal
region (residues 1-8), and differs from other chemokines in the packing of the
hydrophobic core and surface charge distribution. Results with analogs showed
that the N-terminal eight residues formed an important receptor binding site;
however, only Lys-1 and Pro-2 were directly involved in receptor activation.
Modification to Lys-1 and/or Pro-2 resulted in loss of activity, but generated
potent SDF-1 antagonists. Residues 12-17 of the loop region, which we term the
RFFESH motif, unlike the N-terminal region, were well defined in the SDF-1
structure. The RFFESH formed a receptor binding site, which we propose to be an
important initial docking site of SDF-1 with its receptor. The ability of the
SDF-1 analogs to block HIV-1 entry via CXCR4, which is a HIV-1 coreceptor for
the virus in addition to being the receptor for SDF-1, correlated with their
affinity for CXCR4. Activation of the receptor is not required for HIV-1
inhibition.
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Figure 1.
Figure 1 The structure of SDF-1. (A) A stereoview of a
superimposition of the 30 simulated annealing structures of
SDF-1 on the average structure. The RMS deviation for residues 9
-65 between all 30 structures and the average structure is 0.35
Å for backbone and 0.96 Å for heavy atoms. (B) A schematic
diagram showing the restrained minimized average structure of
SDF-1 created with the program MOLSCRIPT (Kraulis, 1991) and
Raster3D (Merritt and Murphy, 1994).
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Figure 7.
Figure 7 A model for interaction of SDF-1 with CXCR4. A
schematic depicting the interaction of SDF-1 with the receptor
is shown. CXCR4 is shown with the seven helices represented as
cylinders, which are connected by the surface and cytoplasmic
loops. The N-terminal and C-terminal segments of the receptor,
and the N- and C-terminus of SDF-1, are annotated as N and C.
SDF-1 is shown as a MOLSCRIPT diagram. (A) indicates the
receptor and ligand separately prior to any interaction between
the two. (B) indicates interaction of the SDF-1 RFFESH loop
(site 1) with the N-terminal segment of the receptor. The
contact region is shown in blue. Two of the helices are
truncated [compare with (A)] to highlight the binding groove of
the receptor. (C) Shows the N-terminal region (site 2) of SDF-1
bound in groove at the top of the helices (orange). Binding of
the N-terminal region results in activation of the receptor,
which is depicted in (C) by the change in conformation of the
receptor helices compared with (B).
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Embo J
(1997,
16,
6996-7007)
copyright 1997.
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