SNAP output for PDB entry 4z8f [SNAP web server]

PDB-id

4z8f; SNAP-derived features in text and JSON formats; DNAproDB

Class

immune system-DNA

Method

X-ray (1.75 Å)

Summary

Fab structure of antibody s1-15 in complex with ssDNA DNA, 5'-p5(dt)p-3'

Reference

Haji-Ghassemi O, Muller-Loennies S, Rodriguez T, Brade L, Kosma P, Brade H, Evans SV (2015): "Structural Basis for Antibody Recognition of Lipid A: INSIGHTS TO POLYSPECIFICITY TOWARD SINGLE-STRANDED DNA." J.Biol.Chem., 290, 19629-19640. doi: 10.1074/jbc.M115.657874.

Abstract

Septic shock is a leading cause of death, and, results from an inflammatory cascade triggered by the presence of microbial products in the blood. Certain LPS from Gram-negative bacteria are very potent inducers and responsible for a high percentage of septic shock cases. Despite decades of research, mAbs specific for lipid A (the endotoxic principle of LPS) have not been successfully developed into a clinical treatment for sepsis. To understand the molecular basis for the observed inability to translate in vitro specificity for lipid A into clinical potential, the structures of antigen binding fragments of mAbs S1-15 and A6 have been determined unliganded and in complex with lipid A carbohydrate backbone. The two antibodies have separate germ-line origins that generate two markedly different combining-site pockets that are complementary both in shape and charge to the antigen. MAb A6 binds lipid A through both variable light and heavy chain residues, while S1-15 utilizes exclusively the variable heavy chain. Both antibodies bind lipid A such that the GlcN-O6 attachment point for the core oligosaccharide is buried in the combining site, which explains the lack of LPS recognition. Longstanding reports of polyspecificity of anti-lipid A antibodies towards single stranded DNA combined with observed homology of S1-15 and A6 and the reports of several single stranded DNA-specific mAbs prompted the determination of the structure of S1-15 in complex with ssDNA fragments, which may provide clues into the genesis of autoimmune diseases such as systemic lupus erythematosus, thyroiditis, and rheumatic autoimmune diseases.