Affiliation:
1. FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff,
UK
Abstract
AbstractThe availability of human monoclonal antibodies (MAbs) to the TSHR has enabled
major advances in our understanding of how TSHR autoantibodies interact with the
receptor. These advances include determination of the crystal structures of the
TSHR LRD in complex with a stimulating autoantibody (M22) and with a blocking
type autoantibody (K1-70). The high affinity of MAbs for the TSHR makes them
particularly suitable for use as ligands in assays for patient serum TSHR
autoantibodies. Also, M22 and K1–70 are effective at low concentrations in vivo
as TSHR agonists and antagonists respectively. K1-70 has important potential in
the treatment of the hyperthyroidism of Graves’ disease and Graves’
ophthalmopathy. Small molecule TSHR antagonists described to date do not appear
to have the potency and/or specificity shown by K1-70. New models of the TSHR
ECD in complex with various ligands have been built. These models suggest that
initial binding of TSH to the TSHR causes a conformational change in the
hormone. This opens a positively charged pocket in receptor-bound TSH which
attracts the negatively charged sulphated tyrosine 385 on the hinge region of
the receptor. The ensuing movement of the receptor's hinge region may then cause
activation. Similar activation mechanisms seem to take place in the case of FSH
and the FSHR and LH and the LHR. However, stimulating TSHR autoantibodies do not
appear to activate the TSHR in the same way as TSH.
Subject
Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,General Medicine,Endocrinology, Diabetes and Metabolism
Cited by
45 articles.
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