Four Classes of Ligands Charged Simple Flexible And Complex

Representative ligands of the human family A receptors fall into four major classes when listed according to their molecular weights (Figure 10.1). The small hydro-philic monoamines are charged and superseded by larger and more amphipathic molecules constituting an amorphous group, the more rigid members of which are hydrophobic and behave in a simple fashion according to Law of Mass Action kinetics. The extremely amphiphilic peptide hormones are flexible in everything they do and lead ultimately to the bulky globular proteins capable of complex formation and complex behavior. The descriptive terms — charged, simple, flexible and complex — define the physicochemical properties of the ligands along with their molecular behaviors, biomolecular interactions, receptor pharmacologies, ease of measurement, pharmacodynamics, pharmacokinetics, and whole body behavior.6

Ligand classes 1, 3 and 4 consist of agonists derived from amino acids and group 2 ligands consist of an amorphous mixture of amphipathic lipids, prostaglandins, and nucleotides. The small monoamines in class 1 are amino acids that became more polar and hydrophilic by the introduction of a positive charge or loss of the zwitterion. The proteins in class 4 are chains of amino acids that are long

FIGURE 10.1 Receptor classification according to ligand size and type. The diverse array of ligands which interact with rhodopsin family receptors can be classified according to their physicochemical properties6 into four main classes, which are distinguishable in a table of representative ligands when listed according to molecular weight.

Hormone ligand

MW

CD Monoamine histamine dopamine acetylcholine (muscarinic) noradrenaline 5-HT/serolonln melatonin

153 162 169 176 232

2 Nucleotide/Lipid atfenosine Odenoreieftfor) .'rans-retinoic acid (opsin) arvandamide icannaboid} prastaglandn F2a i'ysc-phosphatidie acid ATP (purinoceptor) plalelel-aclivaling factor (PAF-16)

267 300 346 352 437 507 524

3 Peptide oxytocin (1 S-S) angiotensin II

gonadotrophin-fele8s«ng hormone substance-P

neurotensin endoilwin-1 (2 S-S> galanln

&-endtophin lopiodh cholecystokBuin <CCK-33) neuropeptide Y

ACTH(1-3®>

1007 1046 1182 1347 1673 2492 3158 3506 3946 4272 4541

Globular Protein inlerleuWn-S A (2 S-S} LHihCG «♦ßsubunit (11 S-S) thrombin (4 S-S}

8923 25739 33814

FIGURE 10.1 Receptor classification according to ligand size and type. The diverse array of ligands which interact with rhodopsin family receptors can be classified according to their physicochemical properties6 into four main classes, which are distinguishable in a table of representative ligands when listed according to molecular weight.

enough to adopt a globular molecular structure, largely driven by the most hydrophobic residues escaping from the solvent water molecules and burying themselves in the protein core. N- and 0-glycans further reduce their surface hydrophobicity and enhance solubility.

Peptide chains with less than about 50 amino acids (MW <5000) cannot form the hydrophobic core that produces a stable globular protein. The patches of alternating hydrophobic and hydrophilic amino acids mean that the peptides in class 3 (as well as many class 2 nonpeptidaceous ligands) are therefore extremely amphiphilic and flexible molecules. They adopt different shapes and structures depending upon their environment, forming oligomeric complexes, aligning themselves at the water-lipid interfaces of cell surfaces, or insinuating themselves into proteins.

The placement of the retinal chromophore within the TM helical bundle is presumed to apply to the 7TMRs that bind smaller ligands, whether charged monoamines or amphipathic lipids. Flexible peptides and globular proteins are presumed to interact with the extracellular loops and variously sample the TM binding pockets directly or indirectly. Although flexible peptides and globular proteins are both amino acid polymers, the allometric relationship between sequence length and ligand physicochemistry is not simple. The property boundaries in behavioral characteristics are catastrophic when moving from a smaller flexible amphiphilic peptide to a larger peptide chain that can adopt the formal and restrained structure of a globular protein. These allometric relationships affect all aspects of the pharmacology and biology of the ligands and can be predicted from knowledge of the molecular size and constitution of the ligand alone.6

The great variety in ligands, of receptor subtypes, and the apparently haphazard utilization of G proteins, is confusing in its profligacy and has hindered the holistic comprehension of ligand-induced signal transduction in these receptors. The classification of receptors according to ligand size provides a perspective useful for biological comprehension, orphan allocation, and drug discovery initiatives.7 As explained in the next section, this functional classification is supported by phyloge-netic evidence.

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