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PDBsum entry 1tzn
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Toxin receptor/toxin
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PDB id
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1tzn
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Contents |
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(+ 8 more)
552 a.a.
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(+ 8 more)
181 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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Structure of heptameric protective antigen bound to an anthrax toxin receptor: a role for receptor in ph-Dependent pore formation.
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Authors
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D.B.Lacy,
D.J.Wigelsworth,
R.A.Melnyk,
S.C.Harrison,
R.J.Collier.
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Ref.
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Proc Natl Acad Sci U S A, 2004,
101,
13147-13151.
[DOI no: ]
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PubMed id
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Abstract
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After binding to cellular receptors and proteolytic activation, the protective
antigen component of anthrax toxin forms a heptameric prepore. The prepore later
undergoes pH-dependent conversion to a pore, mediating translocation of the
edema and lethal factors to the cytosol. We describe structures of the prepore
(3.6 A) and a prepore:receptor complex (4.3 A) that reveal the location of
pore-forming loops and an unexpected interaction of the receptor with the
pore-forming domain. Lower pH is required for prepore-to-pore conversion in the
presence of the receptor, indicating that this interaction regulates
pH-dependent pore formation. We present an example of a receptor negatively
regulating pH-dependent membrane insertion.
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Figure 1.
Fig. 1. The (PA[63])[7] prepore structure. (a) A single
monomer from the 3.6-Å (PA[63])[7] structure. Domains 1,
2, 3, and 4 are colored in pink, green, yellow and blue,
respectively. The previously unresolved 303-322 (red), 343-350
(blue) and 512-515 (blue) loops are visible whereas the 275-283
and 426-427 loops remain unstructured (black dotted lines). (b)
An aerial view (domain 1' is at the top, closest to the viewer)
of the PA[63] heptamer with one monomer colored as in a. Domain
2 lines the prepore lumen whereas domains 3 and 4 are located on
the outside of the heptamer ring. (c) Domains 2 (green) and 4
(blue) from the 3.6-Å (PA[63])[7] structure, as viewed
from the bottom. The domain 2 insertion loop (red) projects out
to bind the neighboring monomer in a groove between domains 2
and 4. (d) The domain 2 insertion loop contacts domain 4 from
its own monomer (residues 600-602) and domains 2 (residue 414)
and 4 (residues 668-670) from the neighboring monomer. N306 was
mutated to cysteine and labeled with pyrene for the experiments
described in Fig. 3b. Residues F313 and F314 are predicted to
form the tip of the membrane inserted  -hairpin (10).
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Figure 2.
Fig. 2. The (PA[63])[7](CMG2)[7] structure. (a) In these
bottom and side views, the CMG2 VWA domains are depicted in
pink. Only three PA:CMG2 monomers are shown in the side view for
clarity. (b) The CMG2 VWA domain (pink) binds both PA domain 2
(white, green, and dark blue) and PA domain 4 (light and dark
blue). Direct contacts within the interface are depicted in dark
pink (CMG2) and dark blue (PA). The PA insertion loop and the
contiguous 2 2 and 2 3 -strands
(green) are predicted to peel away from the domain 2 -barrel
core to form a pore. The CMG2 VWA domain bound to the PA 340-348
loop is likely to impede this rearrangement. (c) This close-up
of the PA:CMG2 interface is colored as in b. Previous PA
mutagenesis studies suggest the importance of residues G342,
W346, I656, N682, and D683 (blue) in intoxication, although the
G342C and W346C mutants may reflect structural instability (16).
The domain 2 R344 (blue) is buried within the PA:CMG2 interface
and may form a salt bridge with CMG2 E122 (pink). Residues Y119,
H121, E122, and Y158 of CMG2 (pink) are strictly conserved in
ATR/TEM8 and cluster at the PA domain 2 interface, suggesting
that ATR/TEM8 binding will also block PA insertion loop
rearrangement. Other CMG2 residues at the interface with PA
(yellow) are not conserved in ATR/TEM8.
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