2M7P

RXFP1 utilises hydrophobic moieties on a signalling surface of the LDLa module to mediate receptor activation

2M7P の概要

• エントリーDOI: 10.2210/pdb2m7p/pdb
• NMR情報: BMRB: 19200
• 分子名称: Low-density lipoprotein receptor, Relaxin receptor 1, CALCIUM ION (2 entities in total)
• 機能のキーワード: rxfp1, relaxin, ldla, protein binding
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 4590.05

構造登録者

Kong, R.CK.,Petrie, E.J.,Mohanty, B.,Ling, J.,Lee, J.C.Y.,Gooley, P.R.,Bathgate, R.A.D. (登録日: 2013-04-29, 公開日: 2013-08-14, 最終更新日: 2024-11-13)

主引用文献

Kong, R.C.K.,Petrie, E.J.,Mohanty, B.,Ling, J.,Lee, J.C.,Gooley, P.R.,Bathgate, R.A.D.
The relaxin receptor (RXFP1) utilizes hydrophobic moieties on a signaling surface of its N-terminal low density lipoprotein class A module to mediate receptor activation.
J.Biol.Chem., 288:28138-28151, 2013

PubMed Abstract: The peptide hormone relaxin is showing potential as a treatment for acute heart failure. Although it is known that relaxin mediates its actions through the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1), little is known about the molecular mechanisms by which relaxin binding results in receptor activation. Previous studies have highlighted that the unique N-terminal low density lipoprotein class A (LDLa) module of RXFP1 is essential for receptor activation, and it has been hypothesized that this module is the true "ligand" of the receptor that directs the conformational changes necessary for G protein coupling. In this study, we confirmed that an RXFP1 receptor lacking the LDLa module binds ligand normally but cannot signal through any characterized G protein-coupled receptor signaling pathway. Furthermore, we comprehensively examined the contributions of amino acids in the LDLa module to RXFP1 activity using both gain-of-function and loss-of-function mutational analysis together with NMR structural analysis of recombinant LDLa modules. Gain-of-function studies with an inactive RXFP1 chimera containing the LDLa module of the human LDL receptor (LB2) demonstrated two key N-terminal regions of the module that were able to rescue receptor signaling. Loss-of-function mutations of residues in these regions demonstrated that Leu-7, Tyr-9, and Lys-17 all contributed to the ability of the LDLa module to drive receptor activation, and judicious amino acid substitutions suggested this involves hydrophobic interactions. Our results demonstrate that these key residues contribute to interactions driving the active receptor conformation, providing further evidence of a unique mode of G protein-coupled receptor activation.

PubMed: 23926099
DOI: 10.1074/jbc.M113.499640

実験手法

SOLUTION NMR