Contents

Abstract 192

10.1 Introduction: Not All 7TMRs are GPCRs 192

10.2 Receptor Classification by Ligand Size 193

10.2.1 ABC(DEF) Classification of GPCRs 193

10.2.2 Four Classes of Ligands: Charged, Simple, Flexible, and Complex 194

10.3 Ligand Diversity Classification Conforms to Receptor Phylogeny 196

10.3.1 GRAFS Classification of 7TMRs 196

10.3.2 Rhodopsin Subfamilies Bind Different Classes of Ligand 197

10.4 Structural Flexibilities of Membrane Receptors 198

10.4.1 Lack of Hydrophobic Drive in 7TMRs 198

10.4.2 Cytochrome C Oxidase, Subunit III 199

10.4.3 Aquaporin 201

10.5 Molecular Bioinformatics in Drug Discovery 201

10.5.1 Rhodopsin Structure Revelations 202

10.5.2 Virtual Screening 205

10.6 Sequence and Structural Searches for an Activation Mechanism 207

10.6.1 TM7 and the NPxxY Motif 207

10.6.2 TM3 and the DRY Motif 209

10.6.3 TM3 and the Conserved Cystine Bridge 209

10.7 The Cysteine Shuffle 211

10.8 Redox Control of Receptor Activation 214

10.8.1 Ligands Devoid of Sulfur 214

10.8.2 Ligands Containing Cysteine 216

10.9 Smells Rank as the Smallest 7TMR Agonists 218

10.9.1 Sulfur, Charges, Rings 218

10.9.2 The Essence of Agonism 219

10.10 Bioinformatics with Biological Sense 222

References 222

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