Family Resemblances? Ligand Binding and Activation of Family A and B G-Protein-Coupled Receptors
نویسندگان
چکیده
Over the years, the association of peptide ligands to Family B GPCRs (G-protein coupled receptors) has been characterized by a number of experimental and theoretical techniques. For the PTH (parathyroid hormone) ligand–receptor system, important insight has been provided by photoaffinity labelling experiments and the elucidation of direct contact points between ligand and receptor. Our research has focused on the structural elucidation of the receptor domains shown to be involved in the binding of PTH. Employing a combination of carefully designed receptor domains, solution-state NMR carried out in the presence of membrane mimetics and extensive computer simulations, we have obtained a well-resolved model of the ligand– receptor complex for PTH. Here, we review the development of this model and highlight some inherent limitations of themethods employed and their consequences on interpretation of the ligand–receptor model. PTH (parathyroid hormone) PTH is a major regulator of blood calcium concentration and bone homoeostasis [1,2]. PTH is secreted from the parathyroid glands as an 84-amino-acid protein (approx. molecular mass of 9300 Da). Cleavage in the liver and kidney produces N-terminal fragments of 34, 36 and 37 amino acids which constitute functional domains, retaining high binding affinity and activity. Indeed, PTH-(1–34) is often utilized as the prototype PTH analogue, retaining high affinity for the PTH1R (PTH type 1 receptor) and PTH bone-related activities. The biological role of the C-terminal portion of the hormone is an area of active study. The related hormone, PTHrP (PTH-related protein), binds to and activates PTH1R and has been related to fetal development, as a regulator of placental calcium and formation of cartilage, as well as being associated with malignant tumours, leading to severe hypercalcaemia [3]. PTHrP(1–34) and PTHrP-(1–36) are fully active, and similarly to PTH-(1–34) has been the major focus in studies aimed a elucidation of the association with PTH1R. PTH1R is a member of the Family B family of the GPCRs (G-protein-coupled receptors), mediates the action of PTH and PTHrP. PTH1R is receiving increasing attention as a potential target for therapeutic treatments of disorders of mineral ion homoeostasis and the skeleton, including hyperparathyroidism, humoral hypercalcaemia of malignancy, and osteoporosis [4]. Progress towards the elucidation of
منابع مشابه
Family resemblances? Ligand binding and activation of family A and B G-protein-coupled receptors.
In April 2007, the Biochemical Society held a meeting to compare and contrast ligand binding and activation of Family A and B GPCRs (G-protein-coupled receptors). Being the largest class, Family A GPCRs usually receive the most attention, although a previous Biochemical Society meeting has focused on Family B GPCRs. The aim of the present meeting was to bring researchers of both families togeth...
متن کاملFamily Resemblances? Ligand Binding and Activation of Family A and B G-Protein-Coupled Receptors
The receptor for CGRP (calcitonin gene-related peptide) is a heterodimer between a GPCR (G-proteincoupled receptor), CLR (calcitonin receptor-like receptor) and an accessory protein, RAMP1 (receptor activitymodifying protein 1). Models have been produced of RAMP1 and CLR. It is likely that the C-terminus of CGRP interacts with the extracellular N-termini of CLR and RAMP1; the extreme N-terminus...
متن کاملElastic network normal mode dynamics reveal the GPCR activation mechanism.
G-protein-coupled receptors (GPCR) are a family of membrane-embedded metabotropic receptors which translate extracellular ligand binding into an intracellular response. Here, we calculate the motion of several GPCR family members such as the M2 and M3 muscarinic acetylcholine receptors, the A2A adenosine receptor, the β2 -adrenergic receptor, and the CXCR4 chemokine receptor using elastic netwo...
متن کاملTransmembrane signal transduction by peptide hormones via family B G protein-coupled receptors
Although family B G protein-coupled receptors (GPCRs) contain only 15 members, they play key roles in transmembrane signal transduction of hormones. Family B GPCRs are drug targets for developing therapeutics for diseases ranging from metabolic to neurological disorders. Despite their importance, the molecular mechanism of activation of family B GPCRs remains largely unexplored due to the chall...
متن کاملFamily Resemblances? Ligand Binding and Activation of Family A and B G-Protein-Coupled Receptors
Chemokines are a family of small basic proteins which induce the directed migration of cells, notably leucocytes, by binding to specific GPCRs (G-protein-coupled receptors ). Both chemokines and their receptors have been implicated in a host of clinically important diseases, leading to the notion that antagonism of the chemokine–chemokine receptor network may be therapeutically advantageous. Co...
متن کامل