Hot topics in pharmacology

Recent publications of interest recommended by NC-IUPHAR

2017: Jan | Feb | Mar | Apr | May

May 2017

Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand
(1) Zhang X et al. (2017). Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand. Nat Commun., 8:15383. [PMID:28513578].


Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators
(1) Song G et al. (2017). Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature, doi: 10.1038/nature22378. [Epub ahead of print]. [PMID:28514449].


Structure of the full-length glucagon class B G-protein-coupled receptor
(1) Zhang H et al. (2017). Structure of the full-length glucagon class B G-protein-coupled receptor. Nature, doi: 10.1038/nature22363. [Epub ahead of print]. [PMID:28514451].


Selectivity determinants of GPCR–G-protein binding
(1) Flock et al. (2017). Selectivity determinants of GPCR-G-protein binding. Nature, doi: 10.1038/nature22070. [Epub ahead of print]. [PMID:28489817].


Protein-phospholipid interplay revealed with crystals of a calcium pump

Comments by Steve Alexander (@mqzspa)

Norimatsu and colleagues [1] have used X-ray solvent contrast modulation to assess density maps of four activation statses of SERCA1. Their observations suggest an unexpected movement of the transporter core, which allows an exaggerated ‘waving’ of the cytoplasmic-extended calcium-binding domain during the cycle of calcium transport. Read the full article on our blog

(1) Norimatsu et al. (2017). Protein-phospholipid interplay revealed with crystals of a calcium pump. Nature, 545(7653):193-198. [PMID:28467821].


Consequences Of Natural Perturbations In The Human Plasma Proteome
(1) Sun et al. (2017). Consequences Of Natural Perturbations In The Human Plasma Proteome. bioRxiv, doi:10.1101/134551. [bioRxiv: 134551].


Assessment of the significance of patent-derived information for the early identification of compound–target interaction hypotheses
(1) Senger, S. (2017). Assessment of the significance of patent-derived information for the early identification of compound–target interaction hypotheses. Journal of Chemoinformatics, 9:26, doi: 10.1186/s13321-017-0214-2. [SpringerOpen: view article].


A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures
(1) Wong et al. (2017). A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures. Immunity, 45(2):442-5. [PMID: 27521270].


April 2017

New developments in cryo-electron microscopy reveal the first Class B GPCR active structure in complex with a G protein

Comments by Dr. Fiona H. Marshall (Director & CSO, Heptares Therapeutics) (@aston_fm)

Solving fully active structures in complex with G proteins is challenging. Recent advances in cryo-electron microscopy (cryo-EM) mean that near atomic resolution is becoming possible for protein complexes of smaller molecular size (sub 100kDa). Using the volta phase plate greatly increases the contrast, particularly at the lower end of the molecular size range, meaning that structures of GPCR complexes are now within reach. The first example of this has been published [1]. Read the full article on our blog

(1) Liang et al. (2017). Phase-plate cryo-EM structure of a class B GPCR–G-protein complex. Nature, doi: 10.1038/nature22327. [PMID: 28437792].


Last rolls of the yoyo: Assessing the human canonical protein count
(1) Southan, C. (2017). Last rolls of the yoyo: Assessing the human canonical protein count. F1000Research, 6:448. [F1000: doi:10.12688/f1000research.11119.1].


Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity
(1) Saleheen et al. (2017). Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature, 544(7649):235-239. [PMID: 28406212].


The Drug Repurposing Hub: a next-generation drug library and information resource
(1) Corsello et al. (2017). The Drug Repurposing Hub: a next-generation drug library and information resource. Nat. Med., 23(4):405-408. [PMID: 28388612].


Neurokinin 3 receptor antagonism for menopausal hot flushes

Comments by Chris Southan (@cdsouthan)

Neurokinin B signalling is increased in menopausal women and has been implicated as an important mediator of hot flushes. A phase 2 trial has assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901 (AZD2624)) [1]. Read the full article on our blog

(1) Prague et al. (2017). Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet, S0140-6736(17)30823-1. [PMID: 28385352].


Fish peptide treats cardiovascular disease

Comments by Chris Southan (@cdsouthan)

The novel GPCR peptide ligand Elabela/Toddler (APELA, Ela), first identified in the fish Danio and critical for the development of the heart, has now been identified in the human cardiovascular system. Yang et al. [1] have recently showed that the peptide binds to the apelin receptor in human heart. Read the full article on our blog

(1) Yang et al. (2017). Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of Its Expression in Pulmonary Arterial Hypertension. Circulation, 135(12):1160-1173. [PMID: 28137936].


Crystal structures of human AT2 reveal molecular mechanism for lack of desensitization and internalization

Comments by Anthony Davenport

The intracellular signal transduction processes activated by the angiotensin AT2 receptor, are atypical for a GPCR and different from the AT1 receptor. Although the classic motifs a GPCR are present in AT2 receptor; it fails to demonstrate classic features of G-protein signalling such as desensitization by phosphorylation, and receptor regulation by internalization. Zhang et al. [1] report the crystal structures of human AT2 bound to an AT2-selective ligand and to an AT1 /AT2 dual ligand, capturing the receptor in an active-like conformation. Read the full article on our blog

(1) Zhang et al. (2017). Structural basis for selectivity and diversity in angiotensin II receptors. Nature, 544(7650):327-332. [PMID: 28379944].


The druggable genome and support for target identification and validation in drug development (3rd Apr 2017)
(1) Finan et al. (2017). The druggable genome and support for target identification and validation in drug development. Science Translational Medicine, 29(383) eaag1166. [Science Trans Med: link].


March 2017

FDA allows marketing of tests to provide genetic risk information
The FDA approved genetic testing company 23andMe to sell customers their susceptibility to heritable genetic traits. Many of these are pharmacologically revelevant

FDA news release


Structural insights into adiponectin receptors suggest ceramidase activity

Comments by Steve Alexander (@mqzspa)

Adiponectin receptors, Adipo1 and Adipo2 suggested to exhibit ceramidase activity - based on in silico evidence [1]. Read the full article on our blog

(1) Vasiliauskaité-Brooks et al. (2017). Structural insights into adiponectin receptors suggest ceramidase activity. Nature, 544(7648):120-123. [PMID: 28329765].


Molecular Structure of the Human CFTR Ion Channel
(1) Liu et al. (2017). Molecular Structure of the Human CFTR Ion Channel. Cell, 23;169(1):85-95. [PMID: 28340353].


Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research
(1) Manolio et al. (2017). Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research. Cell, 169(1):6-12. [PMID: 28340351].


Drug Target Ontology to Classify and Integrate Drug Discovery Data
(1) Lin et al. (2017). Drug Target Ontology to Classify and Integrate Drug Discovery Data. bioRxiv, doi:10.1101/117564. [bioRxiv: 117564].


Functional Social network architecture of human immune cells unveiled by quantitative proteomics
(1) Rieckmann et al. (2017). Social network architecture of human immune cells unveiled by quantitative proteomics. Nat. Immunol., 18(5):583-593. [PMID: 28263321].


Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation
(1) Kim et al. (2017). Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation. Cell, 168(6):1053-1064. [PMID: 28283061].


An atlas of human long non-coding RNAs with accurate 5′ ends
(1) Hon et al. (2017). An atlas of human long non-coding RNAs with accurate 5′ ends. Nature, 543(7744):199-204. [PMID: 28241135].


The Ecstacy and Agony of Assay Interference Compounds
(1) Alrich et al. (2017). The Ecstacy and Agony of Assay Interference Compounds. Biochemistry, 56(10):1363-1366. [PMID: 28244742].


Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1

Comments by Prof. Ian Kerr (University of Nottingham) (@iankerr_science)

Despite a flurry of mammalian ATP binding cassette (ABC) transporter structures in the last 2 years the Holy Grail has still been to determine how these diverse proteins interact with their transport substrates. Jue Chen and colleagues at the Rockefeller have now accomplished this for the multidrug resistance protein-1 (MRP1/ABCC1) using advances in high resolution cryo-electron microscopy to show the structures of substrate-free and leukotriene C4 bound protein [1]. Read the full article on our blog

(1) Johnson Z.L., Chen J. (2016). Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1. Cell, 9;168(6):1075-1085.e9. [PMID: 28238471].


The complete structure of an activated open sodium channel
(1) Sula et al. (2017). The complete structure of an activated open sodium channel. Nat. Commun., 8:14205. [PMID: 28205548].


Peripherally administered orexin improves survival of mice with endotoxin shock
(1) Ogawa et al. (2017). Peripherally administered orexin improves survival of mice with endotoxin shock. Elife, 30;5. [PMID: 28035899].


Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling
(1) Alvarez-Curto et al. (2017). Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling. J. Biol. Chem., 291(53):27147-27159. [PMID: 27852822].


Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity
(1) Glukhova et al. (2017). Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity Cell, 168(5):867-877. [PMID: 28235198].


The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes
(1) Simon et al. (2017). The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes. Mol. Pharmacol., 91(5):518-532. [PMID: 28254957].


Pharmacology of Modulators of Alternative Splicing
(1) Bates et al. (2017). Pharmacology of Modulators of Alternative Splicing. Pharmacol. Rev., 69(1):63-79. [PMID: 28034912].


Ligand and Target Discovery by Fragment-Based Screening in Human Cells
(1) Parker et al. (2017). Ligand and Target Discovery by Fragment-Based Screening in Human Cells. Cell, 168(3):527-541. [PMID: 28111073].


Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin
(1) Metcalf et al. (2017). Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med. Chem. Lett., 8(3):321-326. [PMID: 28337324].


Crystal Structure of an LSD-Bound Human Serotonin Receptor
(1) Wacker et al. (2017). Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell, 168(3):377-389. [PMID: 28129538].


Structures of the Human HCN1 Hyperpolarization-Activated Channel
(1) Lee C.H. & MacKinnon R. (2017). Structures of the Human HCN1 Hyperpolarization-Activated Channel. Cell, 168(1-2):111-120. [PMID: 28086084].


Structure of a Pancreatic ATP-Sensitive Potassium Channel
(1) Li et al. (2017). Structure of a Pancreatic ATP-Sensitive Potassium Channel. Cell, 168(1-2):101-110. [PMID: 28086082].


February 2017

A global genetic interaction network maps a wiring diagram of cellular function
(1) Costanzo et al. (2016). A global genetic interaction network maps a wiring diagram of cellular function. Science, 353(6306). [PMID: 27708008].


Orphan receptor ligand discovery by pickpocketing pharmacological neighbors
(1) Ngo et al. (2017). Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nat. Chem. Biol., 13(2):235-242. [PMID: 27992882].


Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists
(1) Zheng et al. (2016). Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature, 540(7633):458-461. [PMID: 27926736].


Intracellular allosteric antagonism of the CCR9 receptor
(1) Oswal et al. (2016). Intracellular allosteric antagonism of the CCR9 receptor. Nature, 540(7633):462-465. [PMID: 27926729].


Visualizing GPCR ‘Megaplexes’ Which Enable Sustained Intracellular Signaling
(1) Marshall F. H. (2016). Visualizing GPCR ‘Megaplexes’ Which Enable Sustained Intracellular Signaling. Trends Biochem Sci, 41(12):985-986. [PMID: 27825513].


Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2
Guide to Pharmacology: Ryanodine receptor family
(1) Peng et al. (2016). Novel agonist bioisosteres and common structure-activity relationships for the orphan G protein-coupled receptor GPR139. Sci. Rep., 6, 36681. [PMID: 27830715].


January 2017

The orphan GPR139 receptor is activated by peptides

Comments by David E. Gloriam and Anne Cathrine Nøhr Jensen (Department of Drug Design and Pharmacology, University of Copenhagen)

Two new publications on the orphan class A GPCR, GPR139. The first describing the first combined structure-activity relationships of all surrogate agonists, and a common pharmacophore model for future ligand identification and optimization [1]. The second, showing that the endogenous melanocortin 4 receptor agonists,; adrenocorticotropic hormone and α- and β-melanocyte stimulating hormone in the low micromolar range. In addition, a potentially novel subpeptide (from consensus cleavage site) represents the most potent putative endogenous activator, so far (EC50 value of 600 nM) [2]. Read the full article on our blog

(1) Shehata, M.A. (2016). Novel agonist bioisosteres and common structure-activity relationships for the orphan G protein-coupled receptor GPR139. Sci. Rep., 6, 36681. [PMID: 27830715].

(2) Nøhr, A.C. et al. (2016). The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW. Neurochem Int., 102:105-113. [PMID: 27916541].


X-ray crystallographic study defines binding domains for Ca2+ antagonist drugs and their molecular mechanism of action

Comments by Jörg Striessnig (Department of Pharmacology and Toxicology – Institute of Pharmacy, Universität Innsbruck)

This year witnessed a tremendous progress in our understanding of the structure-function relationship of voltage-gated Ca2+ channels. This is based on the cryo-electron microscopy structure of the rabbit Cav1.1 Ca2+ channel complex at a nominal resolution of 3.6 Å (see Hot Topics Sep 20, 2016) which is now nicely complemented by a study defining the binding domains for Ca2+ antagonist drugs and their molecular mechanism of action at atomic resolution [1]. Read the full article on our blog

(1) Tang et al. (2016). Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature, 537, 117–121. [PMID: 27556947].


Archive of previous years