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This Article Accepted manuscript (PDF) Supplementary Table 1 All Versions of this Article: JME-08-0152v1 42/5/381    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nunez Miguel, R. Articles by Rees Smith, B. Search for Related Content PubMed PubMed Citation Articles by Nunez Miguel, R. Articles by Rees Smith, B.

R Nunez Miguel, FIRS Laboratories, RSR Ltd, Cardiff, United Kingdom
J Sanders, FIRS Laboratories, RSR Ltd, Cardiff, United Kingdom
D Chirgadze, Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
J Furmaniak, FIRS Laboratories, RSR Ltd, Cardiff, United Kingdom
B Rees Smith, FIRS Laboratories, RSR Ltd, Cardiff, United Kingdom

Correspondence: Jadwiga Furmaniak, Email: firs{at}rsrltd.eclipse.co.uk

Abstract

The TSHR ligands M22 (a thyroid stimulating human monoclonal antibody) and TSH, bind to the concave surface of the leucine rich repeats domain (LRD) of the TSHR and here we show that M22 mimics closely the binding of TSH. We compared interactions produced by M22 with the TSHR in the M22-TSHR crystal structure (2.55 Angstrom resolution) and produced by TSH with the TSHR in a TSH-TSHR comparative model. The crystal structure of the TSHR and a comparative model of TSH based on the crystal structure of FSH were used as components to build the TSH-TSHR model. This model was built based on the FSH-FSHR structure (2.9 Angstrom) and then the structure of the TSHR in the model was replaced by the TSHR crystal structure. The analysis shows that M22 light chain mimics the TSH beta chain in its interaction with TSHR LRD, while M22 heavy chain mimics the interactions of the TSH alpha chain. The M22-TSHR complex contains a greater number of hydrogen bonds and salt bridges and fewer hydrophobic interactions than the TSH-TSHR complex, consistent with a higher M22 binding affinity. Furthermore, the surface area, formed by TSHR residues N208, Q235, R255 and N256 has been identified as a candidate target region for small molecules which might selectively block binding of autoantibodies to the TSHR.