GtoPdb pre-release ligands (2020.2)

These are some of the ligands under curation (pre-release) in the Guide to Pharmacology. We expect them to be available on the website at the next database release (2020.2 – no earlier than April 2020).

  •  Ligand ID: 10716
    • Name: PRD_002214
    • 10716
    • IUPAC: benzyl (2Z,4S)-4-[(2S)-4-methyl-2-[(2S)-3-methyl-2-[(2S)-2-[(5-methyl-1,2-oxazol-3-yl)formamido]propanamido]butanamido]pentanamido]-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate
    • RCSB PDB: PRD_002214
    • Comment: PRD_002214 is a peptide-like inhibitor of the main protease (MPRO) of SARS-CoV-2. The structure was obtained from the RCSB Protein Data Bank entry 6LU7 which shows the ligand in complex with the protease. The article describing the work has not yet been published (March 12, 2020), but the inhibitor (also referred to as N3) has been deployed in other MPRO crystallisation studies (Yang et al. (2005))
  • Ligand ID: 10720
    • Name: compound 13b
    • Click here for structure editor
    • IUPAC: Tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)-butan-2-yl)ami-no)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate
    • Coment: Compound 13b is an inhibitor of SARS-CoV-2 main protease (Mpro) [3]. It is a derivative of the prevoiusly reported α-ketoamide inhibitor compound 11r [PMID: 32045235][1]. Compound 13b has an enhanced plasma half-life compared to 11r, plus it exhibits substantial lung tropism and has shown suitability for inhalation-mediated administration.
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Database Release 2020.1

We are pleased to announce our first database release of 2020 – version 2020.1.

Coronavirus (Covid-19)

We have added a new coronavirus page to the Guide to Pharmacology which aims to consolidate key pharmacological information and resources related to coronavirus. We have gathered information from various sources, with an aim to cover as many of the pharmacological strategies being considered as we could find. Links are provided to the key ligands and target pages in GtoPdb (where data is available). The page also provides other useful links and resource. We will aim to keep this page updated in this fast changing situation.


GtoPdb contains a couple of useful tools for searching and visualising pharamcology data – that combine data from ChEMBL with GtoPdb data. In this release we’ve update our site to make accessing the visualisation charts easier

Ligand Activity Charts

This tool provides charts with box plots summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Separate charts are created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

Previously, access to the charts was only found on a ligand’s summary page, under the biological activity tab. We’ve now moved that link so it appears more prominently on these pages.ligSumLink

We have also added a new icon on the ligand list pages which indicated whether there are activity charts available for the ligand. Click the icon takes the users straight to the charts.


New ‘bar-chart’ icon added to ligand list to indicate availability of activity charts


We have published a review of the Guide to Immunopharmacology in Immunology at the start of the year. The review provides a deeper context for how the resource can support research into the development of drugs targeted at modulating immune, inflammatory or infectious components of disease.

Harding, S. D., Faccenda, E., Southan, C., Pawson, A. J., Maffia, P., Alexander, S., Davenport, A. P., Fabbro, D., Levi-Schaffer, F., Spedding, M., & Davies, J. A. (2020). The IUPHAR Guide to Immunopharmacology: connecting immunology and pharmacologyImmunology, 10.1111/imm.13175. Advance online publication.

Content Updates


Ion Channels:


Enzymes and Other Protein Targets:

Guide to Malaria Pharmacology Updates:

  • 3 P. falciparum (3D7) targets have been added to the Antimalarial targets family: PfCLK3, PfPMV and PfNCR1
  • The Antimalarial ligands family now contains a total of 80 ligands tagged as antimalarial in the database

Other Updates

Updated display of ligand clinical trial data

The ligand summary pages have been updated to improve the display of clinical trials information. Key clinical trials involving the ligand are now displayed in a separate table, under the clinical data tab. The table includes link out the clinical trial plus trial title, type, source, curator comments and references.


Approved drug with primary targets download

A new download file of all approved drugs and their primary targets has been added to the download page.

New out-links

  • Marine pharmacology – Marine Pharmacology (Midwestern University): a website aimed at those with an interest in the preclinical and clinical pharmacology of marine compounds and the pharmaceutical potential of the enormous biodiversity of organisms present in the world’s oceans
  • Pharos – Pharos is the user interface to the Knowledge Management Center (KMC) for the Illuminating the Druggable Genome (IDG) program
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Hot Topics: Virtual screening on the crystal structure of the G protein-coupled melatonin MT1 receptor reveals several new chemical scaffolds with biological activity

Melatonin targets two high-affinity receptors, MT1 and MT2, that belong to the G protein-coupled receptor (GPCR) superfamily (1,2). Drugs acting on melatonin receptors are subscribed for circadian disorders (jet lag, shift work, etc.), insomnia and major depression (3). All marketed drugs are non-selective agonists targeting both receptor types so far. Despite large chemical synthesis campaigns over the last 20 years, the pharmacology of melatonin receptors remains poorly explored with few inverse agonistic and signaling pathway-biased compounds and few  selective compounds, in particular for the MT1 type (2,4). This lack of pharmacological tools goes along with a rather poor diversity in terms of chemical scaffolds currently available (5). Put into this context, a virtual screening looked like a very promising approach to increase the diversity of chemical scaffolds for melatonin receptors, especially now that the crystal structure of the MT1 receptor has been solved (6). The outcome of the virtual screening study performed by Stein et al. (7) met these high expectations. Overall, 15 new chemical scaffolds were identified from the primary docking of over 150 million virtual molecules (7). Some of the primary hits had pEC50 values around 1nM, which is remarkable. In terms of functional properties, primary hits and derivatives showed agonistic and inverse agonistic properties with or without selectivity for MT1 and MT2. Two MT1 selective inverse agonists were further validated in vivo regarding their effects on circadian rhythm parameters in mice under free-running conditions, as well as using an experimental re-entrainment protocol corresponding to an ‘east-bound’ jet lag paradigm.

This study is not only of great value for the melatonin receptor field but will also encourage virtual screening approaches on other GPCRs for which high-resolution structures are available. Compared to other GPCR structures, the MT1 template structure has several limitations as it was in the inactive form despite the presence of the 2‐phenylmelatonin agonist, and it was heavily modified with 9 point mutations and several truncations to facilitate expression and stability (7,8). However, a favorable feature of MT1 for virtual docking might be its ligand binding pocket which is rather small and hydrophobic with only two key residues important for high-affinity binding. This limits the number of poses to be screened by virtual docking. Moreover, although the screening was designed to identify MT1 selective compounds, positive hits included also MT2 selective and non-selective compounds suggesting that virtual screening is currently unable to predict type selective compounds. This might also depend on the quality of the receptor structure and the degree of divergence between receptor types.

In conclusion, this article is a nice example of successful virtual screening on GPCRs, one of the desired benefits of crystal structures, that will accelerate the drug development process towards compounds with improved efficacy and target-selectivity.

This study investigated two MT1-selective inverse agonists, UCSF7447 and UCSF3384, and a selective MT2 agonist, UCSF4226, for their affinities.

Comments by Ralf Jockers, Institut Cochin, CNRS, INSERM, Université de Paris, Paris, France, Chair for NC-IUPHAR Subcommitee for Melatonin receptors.

  1. Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev. 2010;62(3):343-380.
  2. Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP. Update on Melatonin Receptors. IUPHAR Review. Br J Pharmacol. 2016;173(18):2702-2725
  3. Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol. 2016;56:361-383.
  4. Cecon E, Oishi A, Jockers R. Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol. 2017;175:3263–3280.
  5. Zlotos DP, Jockers R, Cecon E, Rivara S, Witt-Enderby PA. MT1 and MT2 Melatonin Receptors: Ligands, Models, Oligomers, and Therapeutic Potential. J Med Chem. 2014;57(8):3161-3185.
  6. Stauch B, Johansson LC, McCorvy JD, Patel N, Han GW, Huang XP, Gati C, Batyuk A, Slocum ST, Ishchenko A, Brehm W, White TA, Michaelian N, Madsen C, Zhu L, Grant TD, Grandner JM, Shiriaeva A, Olsen RHJ, Tribo AR, Yous S, Stevens RC, Weierstall U, Katritch V, Roth BL, Liu W, Cherezov V. Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature. 2019;569(7755):284-288.
  7. Stein RM, Kang HJ, McCorvy JD, Glatfelter GC, Jones AJ, Che T, Slocum S, Huang XP, Savych O, Moroz YS, Stauch B, Johansson LC, Cherezov V, Kenakin T, Irwin JJ, Shoichet BK, Roth BL, Dubocovich ML. Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature. 2020. [PMID: 32040955]
  8. Cecon E, Liu L, Jockers R. Melatonin receptor structures shed new light on melatonin research. J Pineal Res. 2019:e12606.
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Hot Topics: Cardiac Ca2+ Channel Regulation in the Fight-or-Flight Response: the monomeric small G-protein as another piece in the puzzle

Thirty eight years after the discovery that injection of the catalytic subunits of cyclic AMP-dependent protein kinase A (PKA) into isolated pig ventricular cardiac myocytes (1) increases the amplitude of L-type Ca2+ current (today known to be formed by Cav1.2 channels, (2)), we are now getting close to understand the responsible molecular mechanism. Initial research that has focused on direct regulatory mechanisms, such as the activation by the α-subunit of the stimulatory heterotrimeric G-protein Gs (3), and direct phosphorylation of the pore-forming α1- or accessory β2-subunit of the Cav1.2 channel has not provided a conclusive answer. β-adrenergic modulation was not (α1 Ser-1928, (4)) or only partially (α1 Ser-1700/Thr-1704, (5)) prevented in mutant mice lacking predicted phosphorylation sites in α1 or β2 subunits (6). This was further supported by an elegant transgenic approach showing that expression of channel complexes with all PKA consensus sites mutated to alanine in the Cav1.2 α1 and the β2 subunits (7) has no effects on β-adrenergic modulation.

Assuming that other proteins may be involved in this regulatory pathway, Liu et al. (7) used a biotinylation-based proteomic proximity assay to identify proteins in the Cav1.2 neighborhood regulated by isoproterenol treatment in cardiomyocytes. This led to the discovery of the small Ras-like G protein Rad as a potential candidate. It belongs to the family of the Rad, Rem, Rem2 and Gem/Kir (RGK) Ras-like GTP-binding proteins, which were shown earlier to inhibit high-voltage-activated Ca2+ channels by binding to their β-subunits. Indeed, Rad appears to be the long-sought missing piece in the puzzle: in HEK293T Rad-mediated inhibition of cardiac Cav1.2 channels was relieved by PKA phosphorylation. Modulation was prevented either by the simultaneous mutation of the known cardiac PKA phosphorylation sites of Rad to alanine or by inhibiting the interaction of Rad with the β-subunit.

This mechanism may be universal and may also explain the PKA modulation of other types of β-subunit associated high-voltage activated Ca2+ channels in Rad expressing cells. It also provides evidence that the mechanism of PKA modulation of Cav1.2 Ca2+ channels appears to differ in different cell types. Clearly, direct phosphorylation of Ser-1928 of the α1-subunit is not required for β-adrenergic regulation of Cav1.2 in the heart (4,7). However, this residue is required for β-adrenergic stimulation of Ca2+ channels in hippocampal neurons and for hyperglycaemia-induced stimulation of Ca2+ currents in arterial smooth muscle cells (8,9).

Despite compelling evidence for this novel mechanism, several questions remain: First, what is the role of Rad-dependent modulation of the cardiac L-type channel in intact cardiomyocytes, for example in cardiomyocytes expressing Rad with mutated PKA phosphorylation sites. Second, what is the relative importance of Rad versus modulation by direct phosphorylation of Ser-1700 (and Thr-1704), which has also been found to confer some of the PKA activation of L-type current in cardiomyocytes of Ser1700Ala mutant mice (5).

Despite these open questions, we are now getting close to understand the molecular mechanisms underlying the fight-or-flight response.

Comments by Jörg Striessnig, University of Innsbruck, Chair for NC-IUPHAR Subcommitee for Voltage-gated calcium channels, Liaison for NC-IUPHAR subcommittees on Voltage-gated ion channels

  1. Osterrieder W, Brum G, Hescheler J, Trautwein W, Flockerzi V, Hofmann F. (1982) Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current. Nature 298, 576–8.
  2. Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renström E, Wietzorrek G, Berjukov S, et al. (2004) Isoform-specific regulation of mood behavior and pancreatic β cell and cardiovascular function by L-type Ca2+ J Clin Invest. 113: 1430–9.
  3. Yatani A, Codina J, Imoto Y, Reeves JP, Birnbaumer L, Brown AM. (1987) A G protein directly regulates mammalian cardiac calcium channels. Science 238, 1288–92.
  4. Lemke T, Welling A, Christel CJ, Blaich A, Bernhard D, Lenhardt P, et al. (2008) Unchanged beta-adrenergic stimulation of cardiac L-type calcium channels in Cav1.2 phosphorylation site S1928A mutant mice. J Biol Chem. 283, 34738–44.
  5. Fu Y, Westenbroek RE, Scheuer T, Catterall WA. (2014) Basal and beta-adrenergic regulation of the cardiac calcium channel Cav1.2 requires phosphorylation of serine 1700. Proc Natl Acad Sci U S A. 111, 16598–603.
  6. Brandmayr J, Poomvanicha M, Domes K, Ding J, Blaich A, Wegener JW, et al (2012) Deletion of the C-terminal phosphorylation sites in the cardiac beta-subunit does not affect the basic beta-adrenergic response of the heart and the Cav1.2 channel. J Biol Chem. 287, 22584–92.
  7. Liu G, Papa A, Katchman AN, Zakharov SI, Roybal D, Hennessey JA, et al. (2020) Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics. Nature 577, 695–700 [PMID: 31969708].
  8. Qian H, Patriarchi T, Price JL, Matt L, Lee B, Nieves-Cintrón M, et al. (2017) Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons. Sci Signal. 10 (463), pii: eaaf9659
  9. Nystoriak MA, Nieves-Cintrón M, Patriarchi T, Buonarati OR, Prada MP, Morotti S, et al. (2017) Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel Cav1.2 and vasoconstriction during acute hyperglycemia and diabetes. Sci Signal. 10(463), pii: eaaf9647


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Hot topics: Cannabinoid receptor stuctures

Two new reports cover further aspects of cannabinoid receptor binding as defined using cryo-EM. These expand on previous reports of the structure of the human CB1 cannabinoid receptor with the antagonists taranabant and  AM6538 bound, and with the agonists MDMB-FUBINACA, AM11542 and AM841 bound. Previously reported also is the structure of the CB2 cannabinoid receptor with the antagonist AM10257 bound.

In the first report (1), a non-selective, high potency agonist WIN55212-2 was bound to a complex of the CB2 cannabinoid receptor with Gi to “complete the set” of agonist- and antagonist-bound versions of CB1 and CB2 receptors. The authors suggest marked similarities in the binding configuration of the agonist WIN55212-2 and the antagonist AM10257. Based on these structures, two novel ligands were generated; one predicted to be an agonist and the other an antagonist. The functional data supported these predictions, although both novel compounds were markedly less potent than their respective positive controls.

In the second report (2), agonist-bound versions of both CB1 and CB2 cannabinoid receptors complexed with Gi were also described to ‘complete and expand the set’. AM12033 is a novel nitrilodimethylheptyl analogue of THC with high affinity at both receptors. Structures using this compound were compared to CB1 receptors bound to the THC-like AM841. The authors suggest similar modes of interaction for agonists at the two receptors, supported by numerous examples of non-selective high potency agonists.

Modelling of the second intracellular loop in both reports suggested a structural basis for the CB2 receptor to couple poorly to Gs. Indeed, a single amino acid variation (L222 in CB1 and P139 in CB2 receptors) was highlighted in both studies and evidenced in the previous literature (

Comments by Prof. Steve Alexander (@mqzspa), University of Nottingham, UK

(1) Xing C. et al. Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G i Signaling Complex. Cell (2020) doi:10.1016/j.cell.2020.01.007 [PMID:32004460]

(2) Hua T. et al. Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures. Cell  (2020) doi:10.1016/j.cell.2020.01.008 [PMID:32004463]


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Hot Topics: A brief update on coronaviruses

The new respiratory coronavirus from Wuhan in China is causing intense research activity in the world. Viruses are evidently associated with respiratory infections ranging in severity from the common cold to pneumonia and death. More than 200 viral types have been associated with the common cold, of which 50% of infections are rhinovirus, but also respiratory syncitial virus, influenza – and coronaviruses, particularly human coronavirus-229E (HCoV-229E), which is ‘relatively benign’. Monocytes are relatively resistant to HcoV-229E infection, but rapidly invades, replicates in, and kills dendritic cells within a few hours of infection (Mesel-Lemoine et al., 2012) [1]. Dendritic cells are the sentinel cells in the respiratory tract, and plasmacytoid dendritic cells are a crucial antiviral defence via interferon production. Thus, these viruses can impair control of viral dissemination and the formation of long-lasting immune memory. The cellular receptor for HcoV-229E is CD-13 (aminopeptidase-N).
The cellular receptors for coronaviruses are critical for cell entry. Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and HCoV-NL63, bind to angiotensin converting enzyme2, ACE2, on ciliated cells in the respiratory tract, the crystal structure is known (Song et al., 2018) [2]. The SARS-CoV spike (S) glycoprotein (with S1 and S2 sub-units) on the outer envelope binds to ACE2, fusing viral and cellular membranes, triggering conformational transformations. Cleavage of the S1/S2 subunits by proteases is critical. Indeed, Simmons et al (2005) [3] showed that SARS-CoV infection involved receptor binding, conformational changes receptor binding and subsequent cathepsin L (and type II transmembrane serine proteases) proteolysis within endosomes – with inhibitors of cathepsin L preventing viral entry. SARS-CoV may lead to markedly elevated cytokine levels, leading to tissue damage, pneumonitis, and acute respiratory distress syndrome (ARDS). The spike proteins in SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) are crucial for host specificity and jumping between species, e.g. from bats to humans (Lu et al., 2015) [4], and also the recent cross-over to swine acute diarrhoea syndrome coronavirus (SADS-CoV) to pigs (Zhou et al., 2018) [5]. There is intense interest in the complicated ways whereby coronaviruses engage with their target receptors, are activated and replicate. The rapid evolution of coronaviruses is critical as humans have little or no pre-existing immunity SARS- or MERS-CoV.

ACE2 has been identified as a potential receptor for the novel coronavirus that was identified as the cause of the respiratory disease outbreak in Wuhan in late 2019 (referred to as 2019 – nCoV by the WHO, or Wuhan coronavirus) [6,7 & 9]. 2019-nCoV is a betacoronavirus, and, in common with the SARS-CoV [8], the viral spike protein is postulated to engage ACE2 for viral entry [7]. The data presented by Letko and Munzter [7] is preliminary and has not been peer-reviewed, but a rapid pace of research is needed in the present circumstances. For example, in another recent, preliminary report, ACE2 receptor expression is highly expressed in type II alveolar cells (AT2) with much individual variation and the authors reported that the cells also expressed many genes involved in viral reproduction and transmission [10]. While these findings are preliminary, the rapid publications in bioRxiv and similar archives are crucial in what is now officially a global health emergency. This report is a hot topic in the IUPHAR/BPS Guide to PHARMACOLOGY (, and further underlines the importance of immunopharmacology and the IUPHAR Guide to IMMUNOPHARMACOLOGY (

Comments by Prof. Michael Spedding, Spedding Reseach Solutions; Prof. Steve Alexander (@mqzspa), University of Nottingham; Dr. Elena Faccenda, University of Edinburgh; and Prof. Francesca Levi-Schaffer, The Hebrew University of Jerusalem.

Note from bioRxiv: bioRxiv is receiving many new papers on coronavirus 2019-nCoV.   A reminder: these are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.


  1. Mesel-Lemoine M, Millet J, Vidalain PO, Law H, Vabret A, Lorin V, Escriou N, Albert ML, Nal B, Tangy F. A human coronavirus responsible for the common cold massively kills dendritic cells but not monocytes. J Virol. 2012 Jul;86(14):7577-87. doi: 10.1128/JVI.00269-12. Epub 2012 May 2. PubMed PMID: 22553325; PubMed Central PMCID: PMC3416289.
  2. Song W, Gui M, Wang X, Xiang Y. Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog. 2018 Aug 13;14(8):e1007236. doi: 10.1371/journal.ppat.1007236. eCollection 2018 Aug. PubMed PMID: 30102747; PubMed Central PMCID: PMC6107290.
  3. Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11876-81. Epub 2005 Aug 4. PubMed PMID: 16081529; PubMed Central PMCID: PMC1188015.
  4. Lu R, Wang Y, Wang W, Nie K, Zhao Y, Su J, Deng Y, Zhou W, Li Y, Wang H, Wang W, Ke C, Ma X, Wu G, Tan W. Complete Genome Sequence of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) from the First Imported MERS-CoV Case in China. Genome Announc. 2015 Aug 13;3(4). pii: e00818-15. doi: 10.1128/genomeA.00818-15. PubMed PMID: 26272560; PubMed Central PMCID: PMC4536671.
  5. Zhou L, Sun Y, Lan T, Wu R, Chen J, Wu Z, Xie Q, Zhang X, Ma J. Retrospective detection and phylogenetic analysis of swine acute diarrhoea syndrome coronavirus in pigs in southern China. Transbound Emerg Dis. 2019 Mar;66(2):687-695. doi: 10.1111/tbed.13008. Epub 2019 Jan 9. PubMed PMID: 30171801.
  6. Gralinski LE, Menachery VD. Return of the Coronavirus: 2019-nCoV. Viruses. 2020 Jan 24;12(2). pii: E135. doi: 10.3390/v12020135. PubMed PMID: 31991541.
  7. Letko M, Munster V. Functional assessment of cell entry and receptor usage for lineage B β coronaviruses, including 2019-nCoV. bioRxiv 2020.01.22.915660; doi: 10.1101/2020.01.22.915660
  8. Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005 Sep 16;309(5742):1864-8. PubMed PMID: 16166518.
  9. Peng Z, Shi Z-L. (2020) Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. bioRxiv 2020.01.22.914952; doi: 10.1101/2020.01.22.914952
  10. Yu Zhao, Zixian Zhao, Yujia Wang, Yueqing Zhou, Yu Ma, Wei Zuo.Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov bioRxiv 2020.01.26.919985 doi: 10.1101/2020.01.26.919985
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Hot Topics: Cryo-EM structure of a selective T-type calcium channel blocker bound to the Cav3.1 voltage-gated calcium channel

Nieng Yan’s group has now published the cryo-EM structure of the selective T-type Ca2+ channel blocker Z944 bound to the pore-forming α1-subunit of Cav3.1 T-type Ca2+ channels (1). This nicely adds to recent publications reporting of the high-resolution structures of L-type Ca2+ channel blockers (nifedipine, nimodipine, amlodipine, verapamil, diltiazem) bound to the rabbit Cav1.1 skeletal muscle Ca2+ channel (2) and to the model Ca2+ channel CavAb (Ca2+-selectivity engineered into the bacterial homotetrameric Na+-channel NavAb; 3, 4).

Together these three publications provide important insight into how small molecule channel blockers interact with their high affinity binding domains within Ca2+ channels. They also reveal a remarkable similarity between the core structures (i.e. the voltage-sensors and the pore domains) between not only the closely related Cav1.1 and Cav3.1 channels but also their bacterial ancestor CavAb.

Moreover, although some differences exist, the binding poses of L-type Ca2+ channel blockers in the mammalian Cav1.1 and the bacterial CavAb channel are very similar. In both structures verapamil and diltiazem bind within the central cavity, compatible with their pore-blocking properties predicted in functional studies. In contrast, dihydropyridines like nimodipine and nifedipine bind within a fenestration created by adjacent transmembrane S6 helices (IIIS6 and IVS6). These fenestrations penetrate the sides of the central cavities in both voltage gated Na+– and Ca2+ channels and connect them to the surrounding lipid bilayer of the plasma membrane (5). In accordance with functional studies, these dihydropyridines must therefore inhibit L-type channels by allosterically interfering with gating rather than pore block.

These findings raise the important question about how Z944 can selectively inhibit T-type Ca2+ channels. This drug is currently in clinical development for the treatment of epilepsy and neuropathic pain. It appears that Z944 bound to Cav3.1 combines the binding modes of both pore blockers and allosteric blockers. Its phenyl ring projects into the fenestration between repeats II and III (similar to nifedipine binding), whereas the other end of the molecule projects down through the central cavity to the intracellular mouth of the pore. A prominent interaction was found with lysine-1462, a residue unique for T-type channels. Its mutation to L-type residues reduced drug sensitivity in functional studies suggesting that it is one of the determinants for T-type selectivity.

Taken together the accumulating structural insight into drug binding and modulation will greatly facilitate structure-guided drug discovery. This may lead to new oral subtype-selective blockers of voltage-gated Ca2+ channels with therapeutic potential for the treatment of epilepsy (T-type), pain (T-type, N-type), tremor (T-type), primary aldosteronism (Cav1.3 L-type), progression of Parkinsons disease (Cav1.3, R-type) or rare neurodevelopmental disorders (Cav1.3 L-type) (6,7).

Comments by Jörg Striessnig, University of Innsbruck, Chair for NC-IUPHAR Subcommitee for Voltage-gated calcium channels, Liaison for NC-IUPHAR subcommittees on Voltage-gated ion channels

  1. Zhao, Y., Huang, G., Wu, Q., Wu, K., Li, R., Lei, J., Pan, X., and Yan, N. (2019). Cryo-EM structures of apo and antagonist-bound human Cav3.1. Nature. 576, 492–497 [PMID: 31766050].
  2. Zhao, Y., Huang, G., Wu, J., Wu, Q., Gao, S., Yan, Z., Lei, J., and Yan, N. (2019). Molecular Basis for Ligand Modulation of a Mammalian Voltage-Gated Ca2+ Cell 177, 1495-1506 [PMID: 31150622].
  3. Tang, L., El-Din, T.M.G., Swanson, T.M., Pryde, D.C., Scheuer, T., Zheng, N., and Catterall, W.A. (2016). Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature 537, 117–121 [PMID: 27556947].
  4. Tang, L., Gamal El-Din, T.M., Lenaeus, M.J., Zheng, N., and Catterall, W.A. (2019). Structural Basis for Diltiazem Block of a Voltage-Gated Ca2+ Mol. Pharmacol. 96, 485–492 [PMID: 31391290].
  5. Payandeh, J., Scheuer, T., Zheng, N., Catterall, W.A., 2011. The crystal structure of a voltage-gated sodium channel. Nature 475, 353–358 [PMID: 21743477].
  6. Pinggera, A., and Striessnig, J. (2016). Cav 1.3 (CACNA1D) L-type Ca2+ channel dysfunction in CNS disorders. J. Physiol. (Lond.) 594, 5839–5849.
  7. Benkert, J., Hess, S., Roy, S., Beccano-Kelly, D., Wiederspohn, N., Duda, J., Simons, C., Patil, K., Gaifullina, A., Mannal, N., et al. (2019). Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease. Nat. Commun. 10, 5094. doi:10.1038/s41467-019-12834-x
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