Structure of a Thyrotropin Receptor Monoclonal Antibody Variable Region Provides Insight into Potential Mechanisms for its Inverse Agonist Activity

Thyroid : Official Journal of the American Thyroid Association
Chun-Rong ChenB Rapoport

Abstract

The high constitutive, or ligand-independent, activity of the thyrotropin receptor (TSHR) is of clinical importance in some thyroid conditions, particularly well-differentiated thyroid carcinoma remnants following incomplete ablative therapy (surgery and radioiodine). Under these conditions, even total suppression of TSH by thyroid hormone administration does not fully reduce TSHR activity, a driver of thyrocyte growth. CS-17 is a murine monoclonal antibody that has inverse agonist activity in that it suppresses TSHR constitutive activity. This study crystallized the CS-17 Fab and determined its atomic structure at a resolution of 3.4 Å. In silico docking of this structure to that of the TSHR extracellular domain was accomplished by targeting to TSHR residue tyrosine 195 (Y195) known to contribute to the CS-17 epitope. High affinity interaction between these two molecules, primarily by the CS-17 immunoglobulin heavy chain, was validated by energetic analysis (KD of 8.7 × 10-11 M), as well as by previously obtained data on a number of individual TSHR amino acids in three regions whose mutagenesis reduced CS-17 binding as detected by flow cytometry. Structural insight at atomic resolution of a TSHR antibody with inverse agonist a...Continue Reading

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Citations

Nov 22, 2020·Pharmacological Reviews·Torsten Schöneberg, Ines Liebscher

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Datasets Mentioned

BETA
MH036357
MH036358

Methods Mentioned

BETA
X-ray
flow cytometry

Software Mentioned

XDS
Coot
PRODIGY
Phaser
XSCALE
ZDOCK
BUSTER
CONTACT ( CCP4 )
Phenix

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