3C4M

Structure of human parathyroid hormone in complex with the extracellular domain of its G-protein-coupled receptor (PTH1R)

Summary for 3C4M

• Entry DOI: 10.2210/pdb3c4m/pdb
• Related PRD ID: PRD_900001
• Descriptor: Fusion protein of Maltose-binding periplasmic protein and Parathyroid hormone/parathyroid hormone-related peptide receptor, Parathyroid hormone, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: parathyroid hormone, g-protein-coupled receptor, sugar transport, transport, cleavage on pair of basic residues, disease mutation, secreted, dwarfism, glycoprotein, membrane, receptor, transducer, transmembrane, membrane protein
• Biological source: Escherichia coli (, human); More
• Total number of polymer chains: 4
• Total formula weight: 126372.39

Authors

Pioszak, A.A.,Xu, H.E. (deposition date: 2008-01-30, release date: 2008-04-08, Last modification date: 2024-10-30)

Primary citation

Pioszak, A.A.,Xu, H.E.
Molecular recognition of parathyroid hormone by its G protein-coupled receptor.
Proc.Natl.Acad.Sci.Usa, 105:5034-5039, 2008

PubMed Abstract: Parathyroid hormone (PTH) is central to calcium homeostasis and bone maintenance in vertebrates, and as such it has been used for treating osteoporosis. It acts primarily by binding to its receptor, PTH1R, a member of the class B G protein-coupled receptor (GPCR) family that also includes receptors for glucagon, calcitonin, and other therapeutically important peptide hormones. Despite considerable interest and much research, determining the structure of the receptor-hormone complex has been hindered by difficulties in purifying the receptor and obtaining diffraction-quality crystals. Here, we present a method for expression and purification of the extracellular domain (ECD) of human PTH1R engineered as a maltose-binding protein (MBP) fusion that readily crystallizes. The 1.95-A structure of PTH bound to the MBP-PTH1R-ECD fusion reveals that PTH docks as an amphipathic helix into a central hydrophobic groove formed by a three-layer alpha-beta-betaalpha fold of the PTH1R ECD, resembling a hot dog in a bun. Conservation in the ECD scaffold and the helical structure of peptide hormones emphasizes this hot dog model as a general mechanism of hormone recognition common to class B GPCRs. Our findings reveal critical insights into PTH actions and provide a rational template for drug design that targets this hormone signaling pathway.

PubMed: 18375760
DOI: 10.1073/pnas.0801027105

Experimental method

X-RAY DIFFRACTION (1.95 Å)