1. Molecular model of the PTH(1–34)•PTHR1 complex.
Molecular model of the PTH(1–34)•PTHR1 complex. Shown is a plausible model of PTH(1–34) bound to the PTHR1. The protein backbone chains are shown in ribbon format with the ligand colored magenta and the receptor colored by segment with the amino-terminal extracellular domain (ECD) colored blue-green and the transmembrane domain (TMD) colored by transmembrane helices as follows: purple (TM1), blue (TM2), cyan (TM3), green (TM4), yellow (TM5), orange (TM6), and red (TM7). The structure of the PTH(15–34) in complex with the ECD is according to the structural coordinates reported by Pioszak and Xu (2008) (PDB ID 3C4M). The TMD region of the PTHR1, spanning residues Thre175 to Ser491, was modeled by homology using the crystal structure coordinates of the CRFR1 (Hollenstein et al., 2013) (PDB ID 4K5Y) as a template. The PTH(1–14) segment, modeled as a partial α-helix, was docked to the TMD region manually, placing Val2 and Lys13 of the ligand near the extracellular ends of TMs 6 and 1, respectively. The ECD•PTH(15–34) component was positioned onto the TMD•PTH(1–14) component, manually, allowing for a bend in the ligand between the amino-terminal and carboxyl-terminal domain, as suggested by NMR structural studies on PTH peptide ligands and photoaffinity cross-linking and mutational data on PTH•PTHR1 complexes (Adams et al., 1998; Behar et al., 2000; Marx et al., 2000; Gensure et al., 2001a, 2003; Peggion et al., 2002; Wittelsberger et al., 2006). The side chains of ligand residues Val2, Lys13, Arg20, Trp23, Leu24, and Leu28 are shown in dotted surface format, and the three disulfide bonds in the ECD are in red. The insets show the unliganded ECD and two views of the TMD, rotated 180° relative to each other, which highlight the V-shaped putative ligand-binding groove that forms between the extracellular ends of the TM helices.
Thomas J. Gardella, and Jean-Pierre Vilardaga Pharmacol Rev 2015;67:
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