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PDBsum entry 3esv

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protein Protein-protein interface(s) links
Immune system PDB id
3esv
Jmol
Contents
Protein chains
229 a.a. *
Waters ×286
* Residue conservation analysis
PDB id:
3esv
Name: Immune system
Title: Crystal structure of the engineered neutralizing antibody m18
Structure: Antibody m18 light chain and antibody m18 heavy chain linked with a synthetic (ggggs)4 linker. Chain: f, g. Engineered: yes. Mutation: yes
Source: Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.00Å     R-factor:   0.194     R-free:   0.229
Authors: A.F.Monzingo,C.E.Leysath,J.Barnett,B.L.Iverson,G.Georgiou, J.D.Robertus
Key ref:
C.E.Leysath et al. (2009). Crystal structure of the engineered neutralizing antibody M18 complexed to domain 4 of the anthrax protective antigen. J Mol Biol, 387, 680-693. PubMed id: 19361425 DOI: 10.1016/j.jmb.2009.02.003
Date:
06-Oct-08     Release date:   28-Apr-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
No UniProt id for this chain
Struc: 229 a.a.
Key:    Secondary structure  CATH domain

 

 
DOI no: 10.1016/j.jmb.2009.02.003 J Mol Biol 387:680-693 (2009)
PubMed id: 19361425  
 
 
Crystal structure of the engineered neutralizing antibody M18 complexed to domain 4 of the anthrax protective antigen.
C.E.Leysath, A.F.Monzingo, J.A.Maynard, J.Barnett, G.Georgiou, B.L.Iverson, J.D.Robertus.
 
  ABSTRACT  
 
The virulence of Bacillus anthracis is critically dependent on the cytotoxic components of the anthrax toxin, lethal factor (LF) and edema factor (EF). LF and EF gain entry into host cells through interactions with the protective antigen (PA), which binds to host cellular receptors such as CMG2. Antibodies that neutralize PA have been shown to confer protection in animal models and are undergoing intense clinical development. A murine monoclonal antibody, 14B7, has been reported to interact with domain 4 of PA (PAD4) and block its binding to CMG2. More recently, the 14B7 antibody was used as the platform for the selection of very high affinity, single-chain antibodies that have tremendous potential as a combination anthrax prophylactic and treatment. Here, we report the high-resolution X-ray structures of three high-affinity, single-chain antibodies in the 14B7 family; 14B7 and two high-affinity variants 1H and M18. In addition, we present the first neutralizing antibody-PA structure, M18 in complex with PAD4 at 3.8 A resolution. These structures provide insights into the mechanism of neutralization, and the effect of various mutations on antibody affinity, and enable a comparison between the binding of the M18 antibody and CMG2 with PAD4.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Superposition of backbone traces of unbound scFv 14B7^ asterisk , 1H, and M18 along with M18 from the antigen–antibody complex. The trace of 14B7^ asterisk is shown in dark blue, 1H in light blue, unbound M18 in red, and M18 from the complex in cyan. CDR loops from the bound M18 are shown thicker in yellow.
Figure 7.
Fig. 7. Affinity maturation mutations of M18 and 1H. The M18 light chain is shown in cyan, and the M18 heavy chain in magenta. The M18 CDR loops are shown in green and labeled. PAD4 is shown in black, and the PAD4 receptor binding loops are shown in red. The L:S56P mutation occurs in both M18 and 1H and is shown as a blue ball. The adjacent residue L:Q55, which is mutated to leucine in 1H, is shown as an orange ball. The remaining M18 variant residues are shown as black balls and labeled.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2009, 387, 680-693) copyright 2009.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20232097 A.Malik, A.Firoz, V.Jha, E.Sunderasan, and S.Ahmad (2010).
Modeling the three-dimensional structures of an unbound single-chain variable fragment (scFv) and its hypothetical complex with a Corynespora cassiicola toxin, cassiicolin.
  J Mol Model, 16, 1883-1893.  
20660775 M.Radjainia, J.K.Hyun, C.E.Leysath, S.H.Leppla, and A.K.Mitra (2010).
Anthrax toxin-neutralizing antibody reconfigures the protective antigen heptamer into a supercomplex.
  Proc Natl Acad Sci U S A, 107, 14070-14074.  
19703971 C.D.Kelly-Cirino, and N.J.Mantis (2009).
Neutralizing monoclonal antibodies directed against defined linear epitopes on domain 4 of anthrax protective antigen.
  Infect Immun, 77, 4859-4867.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.