Agonists and Antagonists of Membrane-Bound Receptors

Membrane-bound receptors of the G protein-coupled receptor (GPCR) family and oligomeric receptors with attached tyrosine kinase domains transmit information from the outside to the inside of the cell, enabling signal transduction. GPCRs are a family of approximately 800 proteins in humans that are targeted by 30% of marketed drugs. They are activated by the binding of an extracellular ligand, and this information is transmitted by conformational changes to a number of different G-proteins that serve as binding partners on the cytosolic side. The extracellular ligands can be agonists by activating the receptor and stabilizing an active conformation, antagonists by preventing the binding of an agonist, or inverse agonists by reducing or turning off the basal activity of the receptor. GPCRs exist in many subtypes and their dysregulation is often associated with disease. Rhodopsin, the light-regulated receptor in the eye, is currently the best studied GPCR. Structures of its inactive and active states are known and show how activation is mediated by conformational rearrangements of amino acids along with restructuring of a water network, leading to movement of transmembrane helices and breaking of salt bridges. This alters the structural properties of the G-protein recognition site. In addition, the structure of rhodopsin when phosphorylated at the C-terminus was elucidated with an arrestin bound to the cytosolic side. Arrestin binding desensitizes the GPCR, which is then stored intracellularly in vesicles. Crystal structures of GPCRs suggest how tiny structural changes lead from the inactive to the active state. Many drugs have been developed to interact with GPCRs regulated by small neurotransmitters. Sartans are potent antihypertensive drugs. They were designed with angiotensin II, an agonist of the peptide-binding AT1 receptor, as a reference. The working hypothesis was that sartans bind analogously to the four C-terminal residues of angiotensin II. Subsequent mutation experiments suggested that the peptide agonist and the small molecule antagonists bind to different regions of the receptor. However, recent structural studies reveal a common binding site with binding modes that deviate from a direct overlap with the C-terminus of angiotensin II. The wealth of nuances of our sense of smell is achieved by the simultaneous detection of odorants at multiple GPCRs with composite and attenuated receptor profiles. Genetic polymorphism of odorant receptors results in attenuated sensitivity of individuals to different odors. Composite receptor profiles and attenuated sensitivity due to genetic polymorphism can also be expected for GPCRs targeted by marketed drugs. Dimerizing or oligomerizing receptors bind growth factors and cytokines and carry a tyrosine kinase domain on the cytosolic side. Upon activation, the kinase domain undergoes autophosphorylation, which initiates kinase-dependent signaling cascades. Activation or suppression of oligomerizing receptors requires ligands that interfere with the binding of macromolecular endogenous ligands. Antibodies have been successfully raised to compete with the natural ligands. Low molecular weight ligands can also be found that modify either the receptor or the macromolecular endogenous ligand to block complex formation. Disulfide tethering and fragment-based approaches have shown initial success in the rational design of such compounds. https://sn.pub/fc8htp