Camel single-domain VH antibody complexed with lysozyme
Camelus dromedarius (camel)
The adaptive immune system protects organisms against infections by recognizing and destroying invading viruses and bacteria . Antibodies , also known as immunoglobulins, are the main building blocks of the adaptive immune system and are synthesized in B cells. They selectively bind to foreign molecules, the antigens, and inactivate them. Application of antibodies as therapeutic agents requires a deep understanding of the interactions occurring in the antibody-antigen complex.
The crystal structure of a camel VH bound to its antigen, lysozyme, that we can see here, offers us a view of a new, and very interesting kind of antibody-antigen interaction. Although antibodies usually comprise two-domain structures, which form the antigen binding interface, the camel VH antibody presented here is a single-domain antibody. Single-domain antibodies are more stable in solution and present a larger potential binding surface, which makes them useful as templates for drug design. Camel VH folds in the typical immunoglobulin framework of a four-stranded beta-sheet packed against a five-stranded beta-sheet. Comparison of its surface to that of mouse and human VH's shows that substitutions of Gly 44 -> Glu , Leu 45 -> Arg and Trp 47 -> Gly Val 37 -> Phe make the molecule more soluble, yet these substitutions do not produce major changes in the backbone structure . More interesting though are comparisons of the hypervariable regions. These regions consist of key amino acid residues that are highly conserved even among the most distantly related species. The hypervariable regions show a small number of conformations, or canonical structures, and in the case of Camel VH, they differ significantly from these. In the first region, CDR1 (residues 26-35), amino acids at positions 28 and 29 are pushed towards the antigen, thus forming an exposed loop (residues 28-32). CDR2 (residues 52-56) seems to adopt a canonical structure 2, which is rather surprising because this structure has never been observed in subgroup III VHs . The most impressive is the structure of the CDR3 region. It forms an extended loop of about 10 amino acids, immobilized by disulfide bonds and tyrosine side chains. This loop penetrates deeply into the lysozyme's cleft. It not only increases the accessible interaction interface but allows the antibody to reach epitopes of "low energy", thus opening doors for the design of antibodies targeting this little explored region.
Protein Data Bank (PDB)
Desmyter, A. Transue, T.R. Ghahroudi, M.A. Thi, M.H. Poortmans, F. Hamers, R. Muyldermans, S. Wyns, L.; "Crystal structure of a camel single-domain VH antibody fragment in complex with lysozyme."; Nature Struct. Biol.; (1996) 3:803-811 PubMed:8784355.
author: Rossen Apostolov