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.

In contrast to other eukaryotes, which manufacture lipoic acid, an essential cofactor for several vital dehydrogenase complexes, within the mitochondrion, we show that the plastid (apicoplast) of the obligate intracellular protozoan parasite Toxoplasma gondii is the only site of de novo lipoate synthesis. However, antibodies specific for protein-attached lipoate reveal the presence of lipoylated proteins in both, the apicoplast and the mitochondrion of T. gondii. Cultivation of T. gondii-infected cells in lipoatedeficient medium results in substantially reduced lipoylation of mitochondrial (but not apicoplast) proteins. Addition of exogenous lipoate to the medium can rescue this effect, showing that the parasite scavenges this cofactor from the host. Exposure of T. gondii to lipoate analogues in lipoate-deficient medium leads to growth inhibition, suggesting that T. gondii might be auxotrophic for this cofactor. Phylogenetic analyses reveal the secondary loss of the mitochondrial lipoate synthase gene after the acquisition of the plastid. Our studies thus reveal an unexpected metabolic deficiency in T. gondii and raise the question whether the close interaction of host mitochondria with the parasitophorous vacuole is connected to lipoate supply by the host.

Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR–G-protein complexes remain unclear. Here we report single-particle cryo-EM structures of human S1P receptor 1 (S1P1) and heterotrimeric Gi complexes formed with bound S1P or the multiple sclerosis (MS) treatment drug Siponimod, as well as human LPA receptor 1 (LPA1) and Gi complexes in the presence of LPA. Our structural and functional data provide insights into how LPA and S1P adopt different conformations to interact with their cognate GPCRs, the selectivity of the homologous lipid GPCRs for S1P versus LPA, and the different activation mechanisms of these GPCRs by LPA and S1P. Our studies also reveal specific optimization strategies to improve the MS-treating S1P1-targeting drugs.

Cathepsin G is a major secreted serine peptidase of neutrophils and mast cells. Studies in Ctsg-null mice suggest that cathepsin G supports antimicrobial defenses but can injure host tissues. The human enzyme has unusual “Janus-faced” ability to cleave peptides at basic (tryptic) as well as aromatic (chymotryptic) sites. Tryptic activity has been attributed to acidic Glu226 in the primary specificity pocket and underlies proposed important functions such as activation of pro-urokinase. However, most mammals, including mice, substitute Ala for Glu226, suggesting that human tryptic activity may be anomalous. To test this hypothesis, human cathepsin G was compared with mouse wild type and humanized active site mutants, revealing that mouse primary specificity is markedly narrower than that of human cathepsin G, with much greater Tyr activity and selectivity and near absence of tryptic activity. It also differs from human in resisting tryptic peptidase inhibitors (e.g., aprotinin), while favoring angiotensin destruction at Tyr4 over activation at Phe8. Ala226Glu mutants of mouse cathepsin G acquire tryptic activity and human ability to activate pro-urokinase. Phylogenetic analysis reveals that the Ala226Glu missense mutation appearing in primates 31–43 million years ago represented an apparently unprecedented way to create tryptic activity in a serine peptidase. We propose that tryptic activity is not an attribute of ancestral mammalian cathepsin G, which was primarily chymotryptic, and that primate-selective broadening of specificity opposed the general trend of increased specialization by immune peptidases and allowed acquisition of new functions.

BackgroundCercarial elastase is the major invasive larval protease in Schistosoma mansoni, a parasitic blood fluke, and is essential for host skin invasion. Genome sequence analysis reveals a greatly expanded family of cercarial elastase gene isoforms in Schistosoma mansoni. This expansion appears to be unique to S. mansoni, and it is unknown whether gene duplication has led to divergent protease function.MethodsProfiling of transcript and protein expression patterns reveals that cercarial elastase isoforms are similarly expressed throughout the S. mansoni life cycle. Computational modeling predicts key differences in the substrate-binding pockets of various cercarial elastase isoforms, suggesting a diversification of substrate preferences compared with the ancestral gene of the family. In addition, active site labeling of SmCE reveals that it is activated prior to exit of the parasite from its intermediate snail host.ConclusionsThe expansion of the cercarial gene family in S. mansoni is likely to be an example of gene dosage. In addition to its critical role in human skin penetration, data presented here suggests a novel role for the protease in egress from the intermediate snail host. This study demonstrates how enzyme activity-based analysis complements genomic and proteomic studies, and is key in elucidating proteolytic function.

The photoelectron (PE) spectrum of PrO(-) exhibits a short 835 ± 20 cm(-1) vibrational progression of doublets (210 ± 30 cm(-1) splitting) assigned to transitions from the 4f(2) [(3)H4] σ6s (2) Ω = 4 anion ground state to the 4f(2) [(3)H4] σ6s Ω = 3.5 and 4.5 neutral states. This assignment is analogous to that of the recently reported PE spectrum of CeO(-), though the 82 cm(-1) splitting between the 4f [(2)F2.5] σ6s Ω = 2 and Ω = 3 CeO neutral states could not be resolved [Ray et al., J. Chem. Phys. 142, 064305 (2015)]. The origin of the transition to the Ω = 3.5 neutral ground state is 0.96 ± 0.01 eV, which is the adiabatic electron affinity of PrO. Density functional theory calculations on the anion and neutral molecules support the assignment. The appearance of multiple, irregularly spaced and low-intensity features observed ca. 1 eV above the ground state cannot be reconciled with low-lying electronic states of PrO that are accessible via one-electron detachment. However, neutral states correlated with the 4f(2) [(3)H4] 5d superconfiguration are predicted to be approximately 1 eV above the 4f(2) [(3)H4] σ6s Ω = 3.5 neutral ground state, leading to the assignment of these features to shake-up transitions to the excited neutral states. Based on tentative hot band transition assignments, the term energy of the previously unobserved 4f(2) [(3)H4] σ6s Ω = 2.5 neutral state is determined to be 1840 ± 110 cm(-1).

A computational investigation of the Mo2O(y)(-) + H2O (y = 4, 5) reactions as well as a photoelectron spectroscopic probe of the deuterated Mo2O6D2(-) product have been carried out to understand a puzzling question from a previous study: Why is the rate constant determined for the Mo2O5(-) + H2O/D2O reaction, the terminal reaction in the sequential oxidation of Mo2O(y)(-) by water, higher than the W2O5(-) + H2O/D2O reaction? This disparity was intriguing because W3O(y)(-) clusters were found to be more reactive toward water than their Mo3O(y)(-) analogs. A comparison of molecular structures reveals that the lowest energy structure of Mo2O5(-) provides a less hindered water addition site than the W2O5(-) ground state structure. Several modes of water addition to the most stable molecular and electronic structures of Mo2O4(-) and Mo2O5(-) were explored computationally. The various modes are discussed and compared with previous computational studies on W2O(y)(-) + H2O reactions. Calculated free energy reaction profiles show lower barriers for the initial Mo2O(y)(-) + H2O addition, consistent with the higher observed rate constant. The terminal Mo2O(y)(-) sequential oxidation product predicted computationally was verified by the anion photoelectron spectrum of Mo2O6D2(-). Based on the computational results, this anion is a trapped dihydroxide intermediate in the Mo2O5(-) + H2O/D2O → Mo2O6(-) + H2/D2 reaction.

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