Hot topics: Social network architecture of human immune cells unveiled by quantitative proteomics

The authors applied high-resolution mass-spectrometry-based proteomics to characterize 28 primary human hematopoietic cell populations in steady and activated states at a depth of >10,000 proteins in total. The protein copy numbers revealed a specialization of immune cells for ligand and receptor expression, thereby connecting distinct immune functions. They discuss the fundamental intercellular communication structures and previously unknown connections between cell types. The publicly accessible (http://www.immprot.org/) proteomic resource provides a framework for the orchestration of cellular interplay and a reference for altered communication associated with pathology.

[1] Rieckmann et al. (2017). Nat. Immunol. doi: 10.1038/ni.3693. [Epub ahead of print]. Social network architecture of human immune cells unveiled by quantitative proteomics. [PMID 28263321].

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Hot topics: Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation.

Abstract: Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies.

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

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Hot topics: An atlas of human long non-coding RNAs with accurate 5′ ends

Using FANTOM5 cap analysis of gene expression (CAGE) data, the authors integrate multiple transcript collections to generate a comprehensive atlas of 27,919 human lncRNA genes with high-confidence 5′ ends and expression profiles across 1,829 samples from the major human primary cell types and tissues. The authors combine their findings to identify 19,175 potentially functional lncRNAs in the human genome.

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

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Hot topics: The Ecstacy and Agony of Assay Interference Compounds

Editorial article in Biochemistry.

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

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Hot topics: Ligand and Target Discovery by Fragment-Based Screening in Human Cells

Description of a platform that marries fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in human cells, many of which can be site-specifically determined.

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

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Database release 2017.2

Our 2nd database release of 2017 was published on 23rd March 2017. It now includes 15019 interactions between 2809 targets and 8832 ligands. For full release statistics see the About the Guide to PHARMACOLOGY page.

Target updates

The major part of the work to update the target family summary pages has been completed in advance of producing the Concise Guide to PHARMACOLOGY 2017/18 from the database, which is due out later this year. For the next version, we have been working towards trying to make the information more concise, and limiting both ligands and further reading to the 5 most useful in many cases. Obviously there are some targets where it makes sense to have more or less than 5 displayed on the summary page, but in any case, all the ligands can still be viewed on the detailed target page, and the website contains more further reading references than are included in the published Concise Guide. We are very grateful to all the contributors and the editors who have provided information.

Since most of our curation effort has gone into these updates, the only GPCR detailed page updates this time are the Gonadotrophin-releasing hormone receptors.

Ligand updates

We have refreshed our PDB ligand links and now have 1283 links from ligands to individual RCSB PDB ligand pages and the crystal structures they are found in, e.g. LSD recently crystalised with 5-HT2B.

Meanwhile, our development team has prepared the following new website features and updates:

Web services updates

The REST web services have been updated and now include interactions web services  providing lists of target-ligand pairs which can be filtered by target/ligand type and properties, binding affinity etc., and references web services which can retrieve references by id or the full interaction reference set.

Graphs comparing ligand activity across species

We have developed new ligand activity graphs comparing activity ranges across species using data extracted from GtoPdb and ChEMBL. These are available via the ‘biological activity’ tab (screenshot 1) on ligand pages but currently only for ligands that are also in ChEMBL. For example, DPCPX (screenshot 2) shows similar activity at A1 receptors across a range of species tested.

DCPCX_ligand_page

Screenshot 1. New link to view charts of activity data on the DPCPX ligand page biological activity tab

DPCPX

Screenshot 2. Chart showing DPCPX ligand activity data from ChEMBL and GtoPdb across 4 species. Mouse-over a plot to see the median, lower and upper quartiles, and minimum and maximum data points for each activity type.

Mouse-over a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is 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.

At the end of the page, below the charts, is a table listing all the data points that were used to build the charts, the source databases, assay details, and links to the original references and PubMed.

The graphs can be useful for comparing data across species when choosing model organisms to use for experiments. For example, the ligand palosuran is known to have 100-fold lower binding inhibitory potency on rat versus human UT receptor (screenshot 3).

Palosuran

Screenshot 3. Palosuran activity at human and rat UT receptors.

Extracting ChEMBL activities

Since ChEMBL contains an enormous amount of data (>14.3 million activities in ChEMBL 22) we have filtered and extracted the most useful data and tried to standardise them to the terms used in GtoPdb. Data are selected according to the following criteria:

  1. The target must have a type of ‘SINGLE PROTEIN’, ‘PROTEIN COMPLEX’, or ‘PROTEIN COMPLEX GROUP’
  2. Affinity types are combined and normalised as follows:
    Kd = Dissociation constant, Kd, K app, K Bind, K calc, Kd’, KD app, KD’, Kd(app), KD50, Kdiss, Relative Kd, Binding constant, K aff, K diss, KD/Ki
    pKd = -Log Kdiss, -Log KD50, pKd, pKD, logKd, -Log Kd, Log Kd, -Log KD, Log KD
    Ki = Adjusted Ki, Ki, ki, Ki app (inact), Ki app, Ki(app), Ki_app, Ki’, Ki”, KI’, K’i, Kiact, Ki high, Ki low, KiH, KiL, Kii, KII, Kic, Ki.c, Ki comp, Ki’ uncomp
    pKi = pKi(app), pKi, -Log K0.5, Log Ki, logKi, -Log Ki, pKiH, pKiL
    IC50 = IC50 app, IC50, IC50 max, I50, Mean IC50, IC50H, IC50L
    pIC50 = pIC50, pIC50(app), -Log I50, logIC50, log IC50, Log IC50, -Log IC50, pI50, pIC50(calc)
    EC50 = EC50
    pEC50 = pEC50 diss, pEC50, -Log EC50, Log EC50, logEC50
    A2 = A2
    pA2 = pA2, pA2(app), pA2 app, pA2/pKB
  3. Raw data (e.g. Kis are converted into their negative log to base 10 values (e.g. pKis)
  4. Activities deemed by ChEMBL curators to be “outside typical range” are ignored (to prevent skew)
  5. Only binding (‘B’) and functional (‘F’) assays are included (no large-scale screening data)

We have tried to be as inclusive as possible with the ChEMBL data, but please note that due to the sheer volume, there will be data that have not yet been manually checked by the ChEMBL curators and we always ask users to refer back to the original references when using the data.

We hope this new feature will be useful to our users, and we welcome any feedback you may have.

Posted in Concise Guide to Pharmacology, Database updates, Technical

Recent IUPHAR reviews on Ang(1-7) coupling with GPCRs, treating systemic autoimmune diseases, and small molecule modulators of adenylyl cyclases

The latest ‘state of the field’ IUPHAR reviews are out in the British Journal of Pharmacology:

Karnik SS, Khuraijam D, Tirupula K, Unal H. (2017) Significance of Ang(1-7) coupling with MAS1 and other GPCRs to the Renin-Angiotensin System: IUPHAR Review 22. Br J Pharmacol. doi: 10.1111/bph.13742. [Epub ahead of print] [PMID:28194766]

Ishii M. (2017) Immunology provides a great success for treating systemic autoimmune diseases – a perspective on immunopharmacology – IUPHAR Review 23. Br J Pharmacol. doi: 10.1111/bph.13784. [Epub ahead of print] [PMID:28299772]

In Pharmacological Reviews, the latest IUPHAR review article is:

Dessauer CW, Watts VJ, Ostrom RS, Conti M, Dove S, Seifert R. (2017) International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases. Pharmacol Rev. 69: 93-139. [PMID:28255005]

These come hot on the heels of the 100th article in Pharm Revs, and the 21st in BJP, discussed in this blog post.

 

 

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