3EW3

the 1:2 complex between a Nterminal elongated prolactin and the extra cellular domain of the rat prolactin receptor

Summary for 3EW3

• Entry DOI: 10.2210/pdb3ew3/pdb
• Descriptor: Prolactin, Prolactin receptor (2 entities in total)
• Functional Keywords: complex, glycoprotein, hormone, lactation, secreted, alternative splicing, membrane, receptor, transmembrane, hormone-hormone receptor complex, hormone/hormone receptor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P01236; Membrane; Single-pass type I membrane protein: P05710
• Total number of polymer chains: 3
• Total formula weight: 75680.19

Authors

Broutin, I.,Jomain, J.B.,England, P.,Goffin, V. (deposition date: 2008-10-14, release date: 2009-11-03, Last modification date: 2024-11-20)

Primary citation

Broutin, I.,Jomain, J.B.,Tallet, E.,van Agthoven, J.,Raynal, B.,Hoos, S.,Kragelund, B.B.,Kelly, P.A.,Ducruix, A.,England, P.,Goffin, V.
Crystal structure of an affinity-matured prolactin complexed to its dimerized receptor reveals the topology of hormone binding site 2.
J.Biol.Chem., 285:8422-8433, 2010

PubMed Abstract: We report the first crystal structure of a 1:2 hormone.receptor complex that involves prolactin (PRL) as the ligand, at 3.8-A resolution. Stable ternary complexes were obtained by generating affinity-matured PRL variants harboring an N-terminal tail from ovine placental lactogen, a closely related PRL receptor (PRLR) ligand. This structure allows one to draw up an exhaustive inventory of the residues involved at the PRL.PRLR site 2 interface, consistent with all previously reported site-directed mutagenesis data. We propose, with this description, an interaction model involving three structural components of PRL site 2 ("three-pin plug"): the conserved glycine 129 of helix alpha3, the hydrogen bond network involving surrounding residues (glycine cavity), and the N terminus. The model provides a molecular basis for the properties of the different PRL analogs designed to date, including PRLR antagonists. Finally, comparison of our 1:2 PRL.PRLR(2) structure with those of free PRL and its 1:1 complex indicates that the structure of PRL undergoes significant changes when binding the first, but not the second receptor. This suggests that the second PRLR moiety adapts to the 1:1 complex rather than the opposite. In conclusion, this structure will be a useful guiding tool for further investigations of the molecular mechanisms involved in PRLR dimerization and activation, as well as for the optimization of PRLR antagonists, an emerging class of compounds with high therapeutic potential against breast and prostate cancer.

PubMed: 20053995
DOI: 10.1074/jbc.M109.089128

Experimental method

X-RAY DIFFRACTION (3.8 Å)