title: Structural basis for ligand recognition and discrimination of a quorum-quenching antibody.
abstract: 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.
authors: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Robert N
authors: RN
authors: Kirchdoerfer
authors: Amanda L
authors: AL
authors: Garner
authors: Caralyn E
authors: CE
authors: Flack
authors: Jenny M
authors: JM
authors: Mee
authors: Alexander R
authors: AR
authors: Horswill
authors: Kim D
authors: KD
authors: Janda
authors: Gunnar F
authors: GF
authors: Kaufmann
authors: Ian A
authors: IA
authors: Wilson
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray / Q000379:methods; D015964:Gene Expression Regulation, Bacterial; D007128:Immunoglobulin Fragments / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry; D008024:Ligands; D008164:Luminescent Proteins / Q000378:metabolism; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D025941:Protein Interaction Mapping; D053038:Quorum Sensing / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000235:genetics*
chemical_list: D001426:Bacterial Proteins; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D008024:Ligands; D008164:Luminescent Proteins; D010455:Peptides; C054562:yellow fluorescent protein, Bacteria