X-ray crystal structure of a monoclonal antibody that binds to a major autoantigenic epitope on thyroid peroxidase
| Autor: | Jadwiga Furmaniak, B. Rees Smith, J. Sanders, J. Godfrey, E. Hendry, Griffith Taylor, Michael Powell, N. Liddy, Andrew Sullivan, N. Hayakawa, Fiona Grennan-Jones |
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| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular endocrine system endocrine system diseases Chemical Phenomena medicine.drug_class Endocrinology Diabetes and Metabolism Molecular Sequence Data Autoimmune thyroid disease Monoclonal antibody Crystallography X-Ray Autoantigens Iodide Peroxidase Epitope Epitopes Immunoglobulin Fab Fragments Immunoglobulin kappa-Chains Mice fluids and secretions Endocrinology Thyroid peroxidase medicine Animals Humans Amino Acid Sequence Adaptor Proteins Signal Transducing Mice Inbred BALB C biology Molecular Structure Chemistry Physical Autoantibody food and beverages Antibodies Monoclonal Molecular biology Neoplasm Proteins Thyroid hormones Immunoglobulin G embryonic structures biology.protein Female Binding Sites Antibody Carrier Proteins Crystallization Cell Adhesion Molecules |
| Zdroj: | Thyroid : official journal of the American Thyroid Association. 11(12) |
| ISSN: | 1050-7256 |
| Popis: | Thyroid peroxidase (TPO) catalyzes the production of thyroid hormones and is a major autoantigen in autoimmune thyroid disease (AITD). It is believed that the majority of TPO autoantibodies bind to an immunodominant region consisting of two overlapping domains. Precise location of these domains would help our understanding of the interaction between TPO and TPO autoantibodies. 4F5 is a mouse monoclonal antibody (IgG1, kappa) that reacts with high affinity (2.6 x 10(10) mol/L(-1)) with one of the major autoantigenic regions on TPO. Heavy chain genes of 4F5 were from the VH1 germline gene family, germline genes for the D region could not be assigned and the J region was from the JH2 germline. Light chain genes were from Vkappa4/5 and Jkappa2, germline gene families. The Fab fragment of 4F5 was prepared by papain digestion, purified, crystallized, and the structure solved to 1.9 A using molecular replacement. The refined structure had an R factor of 19.5% and a free R factor of 23.9%. Deduced amino acid sequence and amino acid sequence obtained from diffraction analysis were compared and used to finalize the 4F5 Fab model. Structural analysis indicated that the structure of 4F5 is that of a standard Fab and its combining site is flat and is rich in tyrosine residues. Comparison of the structure of 4F5 with that of a TPO autoantibody Fab, TR1.9 suggests that the two antibodies are unlikely to recognise the same structures on TPO. |
| Databáze: | OpenAIRE |
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