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212 a.a.
217 a.a.
Key reference
DOI no: 10.1016/j.jmb.2007.02.081 J Mol Biol 368:1392-1402 (2007) PubMed id: 17400249
Crystal Structures of a Quorum-quenching Antibody. E.W.Debler, G.F.Kaufmann, R.N.Kirchdoerfer, J.M.Mee, K.D.Janda, I.A.Wilson. ABSTRACT
A large number of Gram-negative bacteria employ N-acyl homoserine lactones (AHLs) as signaling molecules in quorum sensing, which is a population density-dependent mechanism to coordinate gene expression. Antibody RS2-1G9 was elicited against a lactam mimetic of the N-acyl homoserine lactone and represents the only reported monoclonal antibody that recognizes the naturally-occuring N-acyl homoserine lactone with high affinity. Due to its high cross-reactivity, RS2-1G9 showed remarkable inhibition of quorum sensing signaling in Pseudomonas aeruginosa, a common opportunistic pathogen in humans. The crystal structure of Fab RS2-1G9 in complex with a lactam analog revealed complete encapsulation of the polar lactam moiety in the antibody-combining site. This mode of recognition provides an elegant immunological solution for tight binding to an aliphatic, lipid-like ligand with a small head group lacking typical haptenic features, such as aromaticity or charge, which are often incorporated into hapten design to generate high-affinity antibodies. The ability of RS2-1G9 to discriminate between closely related AHLs is conferred by six hydrogen bonds to the ligand. Conversely, cross-reactivity of RS2-1G9 towards the lactone is likely to originate from conservation of these hydrogen bonds as well as an additional hydrogen bond to the oxygen of the lactone ring. A short, narrow tunnel exiting at the protein surface harbors a portion of the acyl chain and would not allow entry of the head group. The crystal structure of the antibody without its cognate lactam or lactone ligands revealed a considerably altered antibody-combining site with a closed binding pocket. Curiously, a completely buried ethylene glycol molecule mimics the lactam ring and, thus, serves as a surrogate ligand. The detailed structural delineation of this quorum-quenching antibody will aid further development of an antibody-based therapy against bacterial pathogens by interference with quorum sensing.
Selected figure(s)
Figure 5.
Figure 5. Antibody-combining site of RS2-1G9 (stereoview). Hydrogen bonds are shown as broken lines. Only Fab side chains that contact the lactam ligand (pink) are displayed. The hapten analog satisfies all its functional groups, except for the amide group of the lactam, which is crucial for the observed cross-reactivity of this antibody with an N-acyl homoserine lactone. A plethora of aromatic side chains surrounds the ligand. The residues between Leu^H97 and Asn^H100 of CDR H3 are omitted for clarity.
Figure 7.
Figure 7. Comparison of the molecular surface representation of (a) the lactam complex and (b) the ethylene glycol complex of antibody RS2-1G9 reveals profound differences in the architecture of the antibody-combining site. The lactam and the buried ethylene glycol (EG) are colored pink and yellow, respectively.
The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 368, 1392-1402) copyright 2007. Figures were selected by an automated process.
Literature references that cite this PDB file's key reference
PubMed id Reference
18476783 G.F.Kaufmann, J.Park, and K.D.Janda (2008).
Bacterial quorum sensing: a new target for anti-infective immunotherapy.Expert Opin Biol Ther, 8, 719-724. 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.
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