3H3G

Crystal structure of the extracellular domain of the human parathyroid hormone receptor (PTH1R) in complex with parathyroid hormone-related protein (PTHrP)

Summary for 3H3G

• Entry DOI: 10.2210/pdb3h3g/pdb
• Related: 3C4M
• Related PRD ID: PRD_900001
• Descriptor: Fusion protein of Maltose-binding periplasmic domain and human parathyroid hormone receptor extracellular domain, Parathyroid hormone-related protein, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: gpcr, extracellular domain, pthrp, pth, pthr1, sugar transport, transport, hormone, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 2
• Total formula weight: 63404.48

Authors

Pioszak, A.A.,Xu, H.E. (deposition date: 2009-04-16, release date: 2009-08-11, Last modification date: 2024-11-27)

Primary citation

Pioszak, A.A.,Parker, N.R.,Gardella, T.J.,Xu, H.E.
Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides.
J.Biol.Chem., 284:28382-28391, 2009

PubMed Abstract: Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic alpha-helix to the same hydrophobic groove in the ECD as occupied by PTH, but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally "unwound." The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics.

PubMed: 19674967
DOI: 10.1074/jbc.M109.022905

Experimental method

X-RAY DIFFRACTION (1.94 Å)