Structural basis for ligand recognition and discrimination of a quorum-quenching antibody

J Biol Chem. 2011 May 13;286(19):17351-8. doi: 10.1074/jbc.M111.231258. Epub 2011 Mar 23.


In the postantibiotic era, available treatment options for severe bacterial infections caused by methicillin-resistant Staphylococcus aureus have become limited. Therefore, new and innovative approaches are needed to combat such life-threatening infections. Virulence factor expression in S. aureus is regulated in a cell density-dependent manner using "quorum sensing," which involves generation and secretion of autoinducing peptides (AIPs) into the surrounding environment to activate a bacterial sensor kinase at a particular threshold concentration. Mouse monoclonal antibody AP4-24H11 was shown previously to blunt quorum sensing-mediated changes in gene expression in vitro and protect mice from a lethal dose of S. aureus by sequestering the AIP signal. We have elucidated the crystal structure of the AP4-24H11 Fab in complex with AIP-4 at 2.5 Å resolution to determine its mechanism of ligand recognition. A key Glu(H95) provides much of the binding specificity through formation of hydrogen bonds with each of the four amide nitrogens in the AIP-4 macrocyclic ring. Importantly, these structural data give clues as to the interactions between the cognate staphylococcal AIP receptors AgrC and the AIPs, as AP4-24H11·AIP-4 binding recapitulates features that have been proposed for AgrC-AIP recognition. Additionally, these structural insights may enable the engineering of AIP cross-reactive antibodies or quorum quenching vaccines for use in active or passive immunotherapy for prevention or treatment of S. aureus infections.

Publication types

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

MeSH terms

  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Crystallography, X-Ray / methods
  • Gene Expression Regulation, Bacterial
  • Immunoglobulin Fragments / chemistry
  • Immunoglobulin G / chemistry
  • Ligands*
  • Luminescent Proteins / metabolism
  • Models, Molecular
  • Peptides / chemistry
  • Protein Binding
  • Protein Interaction Mapping
  • Quorum Sensing / genetics*
  • Quorum Sensing / immunology
  • Signal Transduction
  • Staphylococcus aureus / genetics*


  • Bacterial Proteins
  • Immunoglobulin Fragments
  • Immunoglobulin G
  • Ligands
  • Luminescent Proteins
  • Peptides
  • yellow fluorescent protein, Bacteria

Associated data

  • PDB/3QG6
  • PDB/3QG7