Structural basis of allosteric ligand-receptor interactions in the insulin/relaxin peptide family: implications for other receptor tyrosine kinases and G-protein-coupled receptors.
The insulin/relaxin superfamily of peptide hormones comprises 10 members in humans. The three members of the insulin-related subgroup bind to receptor tyrosine kinases (RTKs), while four of the seven members of the relaxin-like subgroup are now known to bind to G-protein-coupled receptors (GPCRs), the so-called relaxin family peptide receptors (RXFPs). Both systems have a long evolutionary history and play a critical role in fundamental biological processes, such as metabolism, growth, survival and longevity, and reproduction. The structural biology and ligand-binding kinetics of the insulin and insulin-like growth factor I receptors have been studied in great detail, culminating in the recent crystal structure of the insulin receptor extracellular domain. Some of the fundamental properties of these receptors, including constitutive dimerization and negative cooperativity, have recently been shown to extend to other RTKs and GPCRs, including RXFPs, confirming kinetic observations made over 30 years ago.
Receptor Systems Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark.
Pierre
P
De Meyts
Lisbeth
L
Gauguin
Angela Manegold
AM
Svendsen
Mazen
M
Sarhan
Louise
L
Knudsen
Jane
J
Nøhr
Vladislav V
VV
Kiselyov
D000494:Allosteric Regulation; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012065:Relaxin / Q000737:chemistry* / Q000378:metabolism*
D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D007334:Insulin-Like Growth Factor I; D012065:Relaxin; D020794:Receptor Protein-Tyrosine Kinases