Crystal structures of a quorum-quenching antibody

J Mol Biol. 2007 May 18;368(5):1392-402. doi: 10.1016/j.jmb.2007.02.081. Epub 2007 Mar 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / chemistry
  • 4-Butyrolactone / metabolism
  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Ethylene Glycol / chemistry
  • Ethylene Glycol / metabolism
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Engineering
  • Protein Structure, Tertiary*
  • Pseudomonas aeruginosa / physiology*
  • Signal Transduction / physiology*


  • Antibodies, Monoclonal
  • Immunoglobulin Fab Fragments
  • homoserine lactone
  • Ethylene Glycol
  • 4-Butyrolactone

Associated data

  • PDB/2NTF
  • PDB/2OP4