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PDBsum entry 1t6b
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Membrane protein/toxin
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PDB id
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1t6b
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Contents |
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* Residue conservation analysis
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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 a complex between anthrax toxin and its host cell receptor.
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Authors
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E.Santelli,
L.A.Bankston,
S.H.Leppla,
R.C.Liddington.
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Ref.
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Nature, 2004,
430,
905-908.
[DOI no: ]
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PubMed id
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Abstract
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Anthrax toxin consists of the proteins protective antigen (PA), lethal factor
(LF) and oedema factor (EF). The first step of toxin entry into host cells is
the recognition by PA of a receptor on the surface of the target cell.
Subsequent cleavage of receptor-bound PA enables EF and LF to bind and form a
heptameric PA63 pre-pore, which triggers endocytosis. Upon acidification of the
endosome, PA63 forms a pore that inserts into the membrane and translocates EF
and LF into the cytosol. Two closely related host cell receptors, TEM8 and CMG2,
have been identified. Both bind to PA with high affinity and are capable of
mediating toxicity. Here, we report the crystal structure of the PA-CMG2 complex
at 2.5 A resolution. The structure reveals an extensive receptor-pathogen
interaction surface mimicking the non-pathogenic recognition of the
extracellular matrix by integrins. The binding surface is closely conserved in
the two receptors and across species, but is quite different in the integrin
domains, explaining the specificity of the interaction. CMG2 engages two domains
of PA, and modelling of the receptor-bound PA63 heptamer suggests that the
receptor acts as a pH-sensitive brace to ensure accurate and timely membrane
insertion. The structure provides new leads for the discovery of anthrax
anti-toxins, and should aid the design of cancer therapeutics.
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Figure 1.
Figure 1: Structure of the PA -CMG2 complex. Two orthogonal
views are shown in ribbon representation. PA is coloured by
domain (I -IV). CMG2 is blue; the metal ion is shown as a
magenta ball. PA domain I is cleaved after receptor binding,
leading to the loss of domain Ia (yellow) and the formation of
PA[63]. All molecular graphics images were generated using the
UCSF Chimera package^29 (http://www.cgl.ucsf.edu/chimera).
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Figure 5.
Figure 5: Hypothetical model of the receptor-bound,
membrane-inserted PA pore. The model is based on the pre-pore
PA[63] crystal structure^6, channel conductance studies8, and
the crystal structure of  -haemolysin19.
The barrel is formed by rearrangement in each monomer of the
segment shown in red in Fig. 3. Each PA[63] monomer is shown in
a different colour. Residues 303 -324 form the membrane-spanning
region of the barrel. Seven copies of the CMG2 I domain bound to
the heptamer are in blue. The  40
Å gap between the CMG2 I domain and the membrane may be occupied
by a 100-residue
domain of CMG2, C-terminal to the I domain, which precedes its
membrane-spanning sequence.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2004,
430,
905-908)
copyright 2004.
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