2OP4

Crystal Structure of Quorum-Quenching Antibody 1G9

Summary for 2OP4

• Entry DOI: 10.2210/pdb2op4/pdb
• Related: 2NTF
• Descriptor: Murine Antibody Fab RS2-1G9 Lambda Light Chain, Murine Antibody Fab RS2-1G9 IGG1 Heavy Chain, 1,2-ETHANEDIOL (3 entities in total)
• Functional Keywords: immunoglobulin, antibody, fab, induced fit, quorum sensing, homoserine lactone, immune system
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 2
• Total formula weight: 47056.32

Authors

Kirchdoerfer, R.N.,Debler, E.W.,Wilson, I.A. (deposition date: 2007-01-26, release date: 2007-05-15, Last modification date: 2024-10-16)

Primary citation

Debler, E.W.,Kaufmann, G.F.,Kirchdoerfer, R.N.,Mee, J.M.,Janda, K.D.,Wilson, I.A.
Crystal Structures of a Quorum-quenching Antibody.
J.Mol.Biol., 368:1392-1402, 2007

PubMed 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.

PubMed: 17400249
DOI: 10.1016/j.jmb.2007.02.081

Experimental method

X-RAY DIFFRACTION (2.85 Å)