4Z8F

Fab structure of antibody S1-15 in complex with ssDNA DNA, 5'-p5(dT)p-3'

Summary for 4Z8F

• Entry DOI: 10.2210/pdb4z8f/pdb
• Related: 4ODT 4ODU 4Z95
• Descriptor: S1-15 Fab (IgG2b) heavy chain, S1-15 Fab (IgG2b kappa) light chain, 5'-D(P*TP*TP*TP*TP*T)-3', ... (4 entities in total)
• Functional Keywords: antibody, fab, carbohydrate, lipid a, dna, immune system-dna complex, immune system/dna
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 4
• Total formula weight: 51275.37

Authors

Haji-Ghassemi, O.,Evans, S.V. (deposition date: 2015-04-08, release date: 2015-06-24, Last modification date: 2024-11-13)

Primary citation

Haji-Ghassemi, O.,Muller-Loennies, S.,Rodriguez, T.,Brade, L.,Kosma, P.,Brade, H.,Evans, S.V.
Structural Basis for Antibody Recognition of Lipid A: INSIGHTS TO POLYSPECIFICITY TOWARD SINGLE-STRANDED DNA.
J.Biol.Chem., 290:19629-19640, 2015

PubMed Abstract: Septic shock is a leading cause of death, and it 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 are 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 both in complex with lipid A carbohydrate backbone and in the unliganded form. 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, whereas 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 toward 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 single-stranded DNA fragments, which may provide clues about the genesis of autoimmune diseases such as systemic lupus erythematosus, thyroiditis, and rheumatic autoimmune diseases.

PubMed: 26085093
DOI: 10.1074/jbc.M115.657874

Experimental method

X-RAY DIFFRACTION (1.75 Å)