PDBsum entry 1t6b

Membrane protein/toxin

PDB id: 1t6b

Contents

Protein chains

676 a.a. *

170 a.a. *

Ligands

PG4

Metals

_MN

_CA ×2

_NA ×2

Waters ×139

* Residue conservation analysis

PDB id:

1t6b

Name:

Membrane protein/toxin

Title:

Crystal structure of b. Anthracis protective antigen complexed with human anthrax toxin receptor

Structure:

Protective antigen. Chain: x. Engineered: yes. Anthrax toxin receptor 2. Chain: y. Fragment: a/i domain. Synonym: capillary morphogenesis protein-2. Cmg-2. Engineered: yes

Source:

Bacillus anthracis. Organism_taxid: 1392. Expressed in: bacillus anthracis. Expression_system_taxid: 1392. Homo sapiens. Human. Organism_taxid: 9606. Gene: antxr2,cmg2. Expressed in: escherichia coli bl21(de3).

Biol. unit:

Dimer (from PQS)

Resolution:

2.50Å R-factor: 0.210 R-free: 0.266

Authors:

E.Santelli,L.A.Bankston,S.H.Leppla,R.C.Liddington

Key ref:

E.Santelli et al. (2004). Crystal structure of a complex between anthrax toxin and its host cell receptor. Nature, 430, 905-908. PubMed id: 15243628 DOI: 10.1038/nature02763

Date:

05-May-04 Release date: 20-Jul-04

Protein chain

P13423  (PAG_BACAN) -  Protective antigen from Bacillus anthracis

Seq: 764 a.a.

Struc: 676 a.a.

Protein chain

P58335  (ANTR2_HUMAN) -  Anthrax toxin receptor 2 from Homo sapiens

Seq: 489 a.a.

Struc: 170 a.a.

DOI no: 10.1038/nature02763

Nature 430:905-908 (2004)

PubMed id: 15243628

Crystal structure of a complex between anthrax toxin and its host cell receptor.

E.Santelli, L.A.Bankston, S.H.Leppla, R.C.Liddington.

ABSTRACT

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.

Selected figure(s)

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).

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.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2004, 430, 905-908) copyright 2004.

Figures were selected by an automated process.