SNAP output for PDB entry 5gkr [SNAP web server]

PDB-id

5gkr; SNAP-derived features in text and JSON formats; DNAproDB

Class

immune system-DNA

Method

X-ray (2.1 Å)

Summary

Crystal structure of sle patient-derived anti-DNA antibody in complex with oligonucleotide

Reference

Sakakibara S, Arimori T, Yamashita K, Jinzai H, Motooka D, Nakamura S, Li S, Takeda K, Katayama J, El Hussien MA, Narazaki M, Tanaka T, Standley DM, Takagi J, Kikutani H (2017): "Clonal evolution and antigen recognition of anti-nuclear antibodies in acute systemic lupus erythematosus." Sci Rep, 7, 16428. doi: 10.1038/s41598-017-16681-y.

Abstract

The evolutional process of disease-associated autoantibodies in systemic lupus erythematosus (SLE) remains to be established. Here we show intraclonal diversification and affinity maturation of anti-nuclear antibody (ANA)-producing B cells in SLE. We identified a panel of monoclonal ANAs recognizing nuclear antigens, such as double-stranded DNA (dsDNA) and ribonucleoproteins (RNPs) from acute SLE subjects. These ANAs had relatively few, but nonetheless critical mutations. High-throughput immunoglobulin sequencing of blood lymphocytes disclosed the existence of sizable ANA lineages shearing critical mutations intraclonally. We further focused on anti-DNA antibodies, which are capable to bind to both single-stranded (ss) and dsDNA at high affinity. Crystal structure and biochemical analysis confirmed a direct role of the mutations in the acquisition of DNA reactivity and also revealed that these anti-DNA antibodies recognized an unpaired region within DNA duplex. Our study unveils the unique properties of high-affinity anti-DNA antibodies that are generated through antigen-driven affinity maturation in acute phase of SLE.