Ligand interactions with family A B and C receptors

The chemical diversity among the endogenous ligands is exceptional (Table 9). They include biogenic amines, peptides, glycoproteins, lipids, nucleotides, ions and proteases. Moreover, the sensation of exogenous stimuli, such as light, odour and taste, is mediated via GPCRs. Ligand size has a profound effect on the nature and location of binding. Large ligands, such as proteins and peptides, bind to the extracellular loop scaffold, while small molecules, including pharmacological agents, bind within the transmembrane region of the receptor. Peptides can exhibit a mixed binding mode whereby they bind primarily to the extracellular loops while part of the structure penetrates the transmembrane region.

Much information about the ligand binding sites has been acquired through mutation studies (Figure 92). The most prominent mutations in this respect comprise:

• Deletion of an amino acid or even a whole part of the amino acid sequence of the receptor.

• Substitution of single amino acids of the receptor by another amino acid (e.g. to change acidic or basic residues by neutral ones for investigating the role of electrostatic interactions).

Table 9 Examples of endogenous ligands for GPCRs. Reprinted from Biochimica Biophysica Acta, 1422, Flower, D. R., Modelling G protein-coupled receptors for drug design, 207-234. Copyright (1999), with permission from Elsevier.

Type of messenger


Biogenic amines (and related compounds) Peptides and proteins



Purines and nucleotides

Excitatory amino acids & ions

Adrenaline, dopamine, histamine, acetylcholine, noradrenaline, tyramine, serotonin, melatonin Angiotensin, bradykinin. bombesin, C3a, C5a, calcitonin, chemokines (MIP-Ia, -ip, -2, -3a. -3P; eotaxin; IP-IO; RANTES; MCP-l, -2, -3, -; 4, -5; interleukin 8; TARC; HCC-I; MDC; MIG; I-TAC; 1-309; TECK; SDF-I; fractalkine; GCP-2; PARC; DC-CKI; Iymphotactin; ENA-78; NAP-2; LIX; ELC EBII; LARC; SLC), cholecystokinin, conopressin, corticotropin-releasing factor, decay- accelerating factor, diuretic hormone, endothelin, enkephalins and endorphins, follitropin, fMLP and other formylated peptides, glycoprotein hormones, fungal mating pheromones, galanin, growth hormone-releasing hormone,growth hormone secretagogue, gastric inhibitory peptide, gastrin, glucagon, gonadotropin-releasing hormone, LH glycoprotein hormone, melanocortin, neuropeptide Y, neurotensin, opioids, oxytocin, thrombin, protease-activated pituitary adenylyl cyclase-activating peptide, PTHrP, secretin, somatostatin, tachykinin, thyrotropin-releasing hormone, glycoprotein hormones, vasopressin, vasotocin, vasoactive intestinal peptide

Anandamide, cannabinoids, leukotrienes, Iysophosphatidic acid, platelet- activating factor prostacyclins, prostaglandins, thromboxanes Adenosine, cAMP, ATP, UTP, ADP, UDP Glutamate, calcium, GABA

• Production of chimaeric receptors, in which part of the amino acid sequence of a receptor is replaced by the corresponding sequence of another, often related receptor.

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