Jochen Balbach
Martin-Luther-University, Germany
Title: Conformational plasticity of the GPCR activating parathyroid hormone
Biography
Biography: Jochen Balbach
Abstract
The parathyroid hormone (PTH) from glands controls the blood calcium and phosphate level via its G-protein coupled receptors (GPCR). PTH, an 84-residue peptide, is intrinsically disordered and adopts an ï¡-helical conformation for N-terminal residues 15-34 upon binding to the extra cellular domain of the receptor. These residues form the core cross-ï¢ structure in fast forming amyloid fibrils, which is possibly a storage form of the PTH hormone and thus a functional amyloid conformation. NMR-detected phosphorylation at the N-terminus of PTH by cell-lysate of parathyroid glands still allows hormone binding to the ectodomain but abolishes GPCR activation in vivo. The same inhibition can be achieved by a Zn2+ anthracenyl-terpyridine complex binding to the N-terminus of PTH. PTH (1-34) is already an approved drug against osteoporosis, where this Zn2+ coordination complex now allows to control receptor activation not by targeting the receptor itself but at the level of its agonist. The N-terminal residues of PTH thus can adopt various functional conformations depending on the local environment including binding partners, posttranslational modifications, or amyloid fibrils, and we found a conformation selective metal coordination complex to inhibit receptor activation.