The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

SUMMARY Angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9 Å resolution. The AT1R-ZD7155 complex structure revealed key structural features of AT1R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.

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The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

This paper, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittees for the angiotensin receptors, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions, and their likely physiological roles in health and disease. More information on these receptor families can be found in the Concise Guide to PHARMACOLOGY Angiotensins are a group of hormonal peptides and include angiotensin II and angiotensin 1-7 produced by the renin angiotensin system. The biology, pharmacology and biochemistry of the receptors for angiotensins were extensively reviewed recently. In the review, the receptor nomenclature committee was not emphatic on designating MAS1 as the angiotensin 1-7 receptor on the basis of lack of classical G protein signalling and desensitization in response to angiotensin 1-7, as well as a lack of consensus on confirmatory ligand pharmacological analyses. A review of recent publications (2013-2016) on the rapidly progressing research on angiotensin 1-7 revealed that MAS1 and two additional receptors can function as 'angiotensin 1-7 receptors', and this deserves further consideration. In this review we have summarized the information on angiotensin 1-7 receptors and their crosstalk with classical angiotensin II receptors in the context of the functions of the renin angiotensin system. It was concluded that the receptors for angiotensin II and angiotensin 1-7 make up a sophisticated cross-regulated signalling network that modulates the endogenous protective and pathogenic facets of the renin angiotensin system.

MAS is a G protein-coupled receptor (GPCR) implicated in multiple physiological processes. Several physiological peptide ligands such as angiotensin-(1–7), angiotensin fragments and neuropeptide FF (NPFF) are reported to act on MAS. Studies of conventional G protein signaling and receptor desensitization upon stimulation of MAS with the peptide ligands are limited so far. Therefore, we systematically analyzed G protein signals activated by the peptide ligands. MAS-selective non-peptide ligands that were previously shown to activate G proteins were used as controls for comparison on a common cell based assay platform. Activation of MAS by the non-peptide agonist (1) increased intracellular calcium and D-myo-inositol-1-phosphate (IP1) levels which are indicative of the activation of classical Gαq-phospholipase C signaling pathways, (2) decreased Gαi mediated cAMP levels and (3) stimulated Gα12-dependent expression of luciferase reporter. In all these assays, MAS exhibited strong constitutive activity that was inhibited by the non-peptide inverse agonist. Further, in the calcium response assay, MAS was resistant to stimulation by a second dose of the non-peptide agonist after the first activation has waned suggesting functional desensitization. In contrast, activation of MAS by the peptide ligand NPFF initiated a rapid rise in intracellular calcium with very weak IP1 accumulation which is unlike classical Gαq-phospholipase C signaling pathway. NPFF only weakly stimulated MAS-mediated activation of Gα12 and Gαi signaling pathways. Furthermore, unlike non-peptide agonist-activated MAS, NPFF-activated MAS could be readily re-stimulated the second time by the agonists. Functional assays with key ligand binding MAS mutants suggest that NPFF and non-peptide ligands bind to overlapping regions. Angiotensin-(1–7) and other angiotensin fragments weakly potentiated an NPFF-like calcium response at non-physiological concentrations (≥100 µM). Overall, our data suggest that peptide ligands induce atypical signaling and functional desensitization of MAS.

High affinity dual antagonist: The envelope glycoprotein gp120 of HIV‐1 mediates the first steps of viral entry into the host cell. An azidoproline‐based peptide conjugate 1 blocks the interaction of gp120 with both the CD4 cell‐surface receptor and 17b (an antibody surrogate of the CCR5 co‐receptor). It represents a potentially effective approach in preventing HIV infection.

Little is known about the general folding mechanisms of helical membrane proteins. Unfolded, i.e. non-native states, in particular, have not yet been characterized in detail. Here, we establish conditions under which denatured states of the mammalian membrane protein rhodopsin, a prototypic G protein coupled receptor with primary function in vision, can be studied. We investigated the effects of the chemical denaturants sodium dodecyl sulfate (SDS), urea, guanidine hydrochloride (GuHCl) and trifluoroacetic acid (TFA) on rhodopsin's secondary structure and propensity for aggregation. Ellipticity at 222nm decreases in the presence of maximum concentrations of denaturants in the order TFA > GuHCl > urea > SDS + urea > SDS. Interpretation of these changes in ellipticity in terms of helix loss is challenged because the addition of some denaturants leads to aggregation. Through a combination of SDS-PAGE, dependence of ellipticity on protein concentration and 1D 1 H NMR we show that aggregates form in the presence of GuHCl, TFA and urea but not in any concentration of SDS, added over a range of 0.05% to 30%. Mixed denaturant conditions consisting of 3% SDS and 8M urea, added in this order, also did not result in aggregation. We conclude that SDS is able to prevent the exposure of large hydrophobic regions present in membrane proteins which otherwise leads to aggregation. Thus, 30% SDS and 3% SDS + 8M urea are the denaturing conditions of choice to study maximally unfolded rhodopsin without aggregation.Membrane proteins are essential for all living systems and include important protein families such as receptors, transporters, ion channels, pumps, and proteins with structural roles or enzymatic activity. In humans, membrane proteins constitute one third of all the proteins (1). Failure of a membrane protein to fold into its native three-dimensional structure can lead to disruption of regulated cell functions and cause diseases (2). There are several pathological conditions such as cystic fibrosis, Charcot-Marie-Tooth disease, hearing loss, and Retinitis Pigmentosa (RP), in which misfolding of membrane proteins has been implicated as contributing to disease (2). Through an understanding of the folding mechanism of membrane proteins it may be possible to identify avenues for the treatment of such diseases. † This work was in part supported by the National Science Foundation CAREER grant CC044917, National Institutes of Health Grant In the field of soluble proteins, characterization of unfolded states has been crucial in understanding mechanisms of folding and indeed has shed light also on misfolding diseases (3,4). An important conclusion is that even under strongly denaturing conditions some interresidue interactions, either native-like or non-native and especially those among hydrophobic residues, are present in the unfolded state (5). Such interactions constitute residual structure in denatured states and are assumed to form during the early stages of folding of a protein, playing crucial role for folding by ac...