1xf3
Structure of ligand-free Fab DNA-1 in space group P65
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OverviewOverview
Anti-DNA antibodies play important roles in the pathogenesis of autoimmune, diseases. They also represent a unique and relatively unexplored class of, DNA-binding protein. Here, we present a study of conformational changes, induced by DNA binding to an anti-ssDNA Fab known as DNA-1. Three crystal, structures are reported: a complex of DNA-1 bound to dT3, and two, structures of the ligand-free Fab. One of the ligand-free structures was, determined from crystals exhibiting perfect hemihedral twinning, and the, details of structure determination are provided. Unexpectedly, five, residues (H97-H100A) in the apex of heavy chain, complementarity-determining region 3 (HCDR3) are disordered in both, ligand-free structures. Ligand binding also caused a 2-4A shift of the, backbone of Tyr L92 and ordering of the L92 side-chain. In contrast, these, residues are highly ordered in the Fab/dT3 complex, where Tyr H100 and Tyr, H100A form intimate stacking interactions with DNA bases, and L92 forms, the 5' end of the binding site. The structures suggest that HCDR3 is very, flexible and adopts multiple conformations in the ligand-free state. These, results are discussed in terms of induced fit and pre-existing equilibrium, theories of ligand binding. Our results allow new interpretations of, existing thermodynamic and mutagenesis data in terms of conformational, entropy and the volume of conformational space accessible to HCDR3 in the, ligand-free state. In the context of autoimmune disease, plasticity of the, ligand-free antibody could provide a mechanism by which anti-DNA, antibodies bind diverse host ligands, and thereby contribute to, pathogenicity.
About this StructureAbout this Structure
1XF3 is a Protein complex structure of sequences from Mus musculus. Full crystallographic information is available from OCA.
ReferenceReference
Evidence for structural plasticity of heavy chain complementarity-determining region 3 in antibody-ssDNA recognition., Schuermann JP, Prewitt SP, Davies C, Deutscher SL, Tanner JJ, J Mol Biol. 2005 Apr 15;347(5):965-78. PMID:15784256
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