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PDBsum entry 3cml
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Membrane protein
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PDB id
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3cml
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References listed in PDB file
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Key reference
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Title
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Structure of the dbl3X domain of pregnancy-Associated malaria protein var2csa complexed with chondroitin sulfate a.
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Authors
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K.Singh,
A.G.Gittis,
P.Nguyen,
D.C.Gowda,
L.H.Miller,
D.N.Garboczi.
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Ref.
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Nat Struct Biol, 2008,
15,
932-938.
[DOI no: ]
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PubMed id
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Abstract
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Plasmodium falciparum-infected erythrocytes bind to chondroitin sulfate A (CSA)
in the placenta via the VAR2CSA protein, a member of the P. falciparum
erythrocyte membrane protein-1 family, leading to life-threatening malaria in
pregnant women with severe effects on their fetuses and newborns. Here we
describe the structure of the CSA binding DBL3x domain, a Duffy binding-like
(DBL) domain of VAR2CSA. By forming a complex of DBL3x with CSA oligosaccharides
and determining its structure, we have identified the CSA binding site to be a
cluster of conserved positively charged residues on subdomain 2 and subdomain 3.
Mutation or chemical modification of lysine residues at the site markedly
diminished CSA binding to DBL3x. The location of the CSA binding site is an
important step forward in the molecular understanding of pregnancy-associated
malaria and offers a new target for vaccine development.
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Figure 2.
(a) View of the CSA electron density near helices H5 and H6.
Residues with side chains within 5 Å of the density are
identified. A sulfate group (sulfur, yellow; oxygen, red) has
been placed in the density and is coordinated by the side chains
of Lys1324, Arg1467 and Lys1504. The 2F[o] – F[c] map (dark
blue) is contoured at 0.9  and
the F[o] – F[c] map (cyan) is contoured at 2.5 .
For clarity, Lys1327 is not shown. (b) Stereo view showing the
CSA density, a sulfate group and the side chains of nearby
residues. The DBL3x model without ligands was used to calculate
phases for these maps.
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Figure 4.
(a) Ribbon diagram of DBL3x overlayed on a semitransparent
electrostatic potential surface. Side chains of lysines and
arginines responsible for the positively charged region are
shown in red. Subdomain 1 (yellow), subdomain 2 (blue) and
subdomain 3 (red) are shown. For clarity, Lys1327 is not shown.
(b) Positively charged areas (blue) are located on the sides of
the binding area for the CSA oligosaccharide, shown in same
orientation as in a. Lysines and arginines with side chains
within 5 Å of the carbohydrate density are labeled (+,
yellow). Below the CSA binding site is a region of negatively
charged residues (red at arrow), which could prevent CSA from
occupying the deeper portions of the 'valley' between subdomains
2 and 3. (c) View of a CSA hexasaccharide model^39 (PDB 1C4S)
placed along the extra electron density seen in the crystals.
The hexasaccharide shown here is approximately 30 Å in
length and similar to the length of the observed electron
density. Lys1327 is shown.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Nat Struct Biol
(2008,
15,
932-938)
copyright 2008.
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