Hot Topic: Structural details for coupling of the agonist-occupied µ opioid receptor (amongst others) to the Gi protein

Every few years in the field of receptor pharmacology, a technological advance occurs that drives the field forward in terms of insight and understanding. Over the past couple of years, the cryo-EM technique (the development of which won the 2017 Nobel Prize in Chemistry for Dubochet, Frank, and Henderson) for resolving protein structures at near atomic resolution has been highlighted as one such approach. Now some of the first papers applying this methodology to G protein-coupled receptors (GPCRs) are beginning to appear. The strength of this approach for GPCRs is revealed in the recent paper by Koehl et al. (1) showing the detailed structure of the agonist-bound µ opioid receptor (GtoPdb target ID 139) coupled to the Gi subtype of G protein. DAMGO (GtoPdb ligand ID 1647), the agonist used in the study, is a selective and efficacious peptide agonist at the µ receptor and is used in many studies as the standard µ receptor agonist. The structure of the DAMGO-µ receptor-Gi complex shows some interesting and unexpected detail, for example, that the binding pocket for Gi at the base of the receptor is smaller, and the outswing of the lower end of TMD VI smaller, than that for GPCRs that couple primarily to Gs proteins.

Apart from the obvious benefits for future drug development at µ receptor, the full impact of the cryo-EM approach for µ receptor structure/function is likely to be felt more in the future, as we can no doubt look forward to the appearance of µ receptor/signalling protein structures with partial agonists as well as biased agonists, and the structure of ligand-bound µ receptor interacting with GRKs or arrestin proteins. The speed at which this field is moving is already breathtaking – in the issue of Nature carrying the DAMGO-µ receptor-Gi cryo-EM report, there are others detailing the structure of activated rhodopsin-Gi (2), adenosine activated adenosine A1-Gi (3) and agonist-activated 5HT1B-Go (4). Recently also the structure of the Class B GLP-1 receptor in complex with a biased ligand and Gs was reported (5). Many more structures of such complexes are likely to follow over the next couple of years, with a corresponding leap forward in our understanding of the structure and function of GPCRs. There are still challenges however; as Koehl and colleagues point out in their groundbreaking paper (1), the nature of the initial interactions of G proteins and other signalling proteins with GPCRs, and the identity of the possibly novel receptor conformations that exist at these early time points in complex formation, remain considerable challenges for both X-ray crystallography and cryo-EM techniques.

Comments by Eamonn Kelly ( and Katy Sutcliffe

(1) Koehl A. et al. (2018). Structure of the μ-opioid receptor–Gi protein complex. Nature, 558. 547–552. [PMID: 29899455]

(2) Kang Y. et al. (2018). Cryo-EM structure of human rhodopsin bound to an inhibitory G protein. Nature, 558. 553-558. [PMID: 29899450]

(3) Draper-Joyce C.J. et al. (2018). Structure of the adenosine-bound human adenosine A1 receptor–Gi complex. Nature, 558. 559–563. [PMID: 29925945]

(4) García-Nafría J. et al. (2018). Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go. Nature, 558. 620-623. [PMID: 29925951]

(5) Liang Y.L. et al. (2018). Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature, 555. 121-125. [PMID: 29466332]

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Posted in Hot Topics

Hot Topic: Systems Medicine, Disease Maps and the future of Systems Biology

What will Systems Biology look like in the future? Up to now, it has focussed on the development of standards, software tools and databases that enabled us to study the dynamics of physiological function mechanistically. However as these tools and technologies have matured, the focus of the systems biology research community has moved towards how they can best be interconnected and exploited to develop our understanding of health and disease across whole cells, tissues, organs, organisms. This version 2.0 of systems biology, will build on the existing technologies to create resources that are more intuitive, more accurate, more accessible and are easier to use for anyone engaged with research.

Disease maps describe the interactions and pathways that are perturbed from healthy physiological function in disease pathophysiology. The Disease Maps consortia, spearheaded by the Luxembourg Centre for Systems Biomedicine, the Institut Curie and the European Institute for Systems Biology and Medicine, are developing rich resources to enable us to understand how healthy function is perturbed across different scales. These include from the molecular to the organismal, and that embed individually perturbed pathways in a wider intra- and inter-cellular network so that the systems and systemic impact can be more easily investigated [1].   Each disease topic is the focus of a community of clinical, laboratory and systems biology expertise and the consortia is organised as a community of communities with the following adopted principles:-

  • Central integration of in vivo and in vitro disease experts across diseases
  • Close integration of pathway mapping and modeling expertise
  • Regular sharing of best practice and expertise across diseases

The consortia embrace open access, standard formats, modularity, consistency of quality and best practices in the field. It is anticipated that this work will deliver resources that can support comprehensive programmes of systems medicine by including the following:

  • Dedicated trusted reference resources describing disease mechanisms that facilitate advanced data interpretation, hypothesis generation, and hypothesis prioritisation.
  • Tools for the study of co- and multi-morbidities, which can deliver refined biomarkers for improved clinical diagnostics.
  • Tools for the study of systems pharmacology that suggest drug repositioning and multi-drug intervention strategies.
  • Novel insights into disease subclassification supporting the development of next-generation disease ontologies.
  • Supporting the design and prototyping of new clinical decision-making strategies.

The Disease Maps consortia thus want to accelerate the development of Systems Biology 2.0 and the roadmap presented in this paper describes how it can be steered towards translational utility.

Comments by Steven Watterson (@systemsbiology), University of Ulster

[1]. Mazein A, Ostaszewski M, Kuperstein I, Watterson S, Le Novère N, Lefaudeux D, De Meulder B, Pellet J, Balaur I, Saqi M, Nogueira MM, He F, Parton A, Lemonnier N, Gawron P, Gebel S, Hainaut P, Ollert M, Dogrusoz U, Barillot E, Zinovyev A, Schneider R, Balling R and Auffray C (2018) Systems medicine disease maps: community-driven comprehensive representation of disease mechanisms, NPG Systems Biology and Applications 4:21. [PMID 29872544]

Posted in Hot Topics

Hot topic: Structure of the adenosine-bound human adenosine A1 receptor–Gi complex

The A1 adenosine receptor is, for most people, a molecular target they can become conscious of when they block it, which happens frequently. Rapid consumption of higher doses of caffeine, in products like Italian espresso or Turkish coffee, provokes a rapid, transient increase in heart rate and a noticeable increase in limb tremor. As the most widely consumed psychoactive substance, caffeine has these effects through blockade of the A1 adenosine receptor, which is found on cardiomyocytes and the peripheral nerve terminals of the sympathetic nervous system (as well as many other locations), leading to an increase in cardiac contractility and noradrenaline release, respectively.

In this report, a 3.6 Å structure of the receptor complexed with the endogenous agonist, adenosine, in the presence of the heterotrimeric G12 protein has been resolved by cryo-EM. As expected, there are differences in conformation compared to the previously-reported antagonist-bound receptor, principally in TM1 and TM2. There are also differences compared to the structure reported for the Gs-coupled, agonist-bound beta2-adrenoceptor.

Comments by Steve Alexander (@mqzspa)

(1) Draper-Joyce C.J. et al. (2018). Structure of the adenosine-bound human adenosine A1 receptor–Gi complex. Nature, 558. 559–563. [PMID: 29925945]

Posted in Hot Topics

Database release 2018.3

Our third database release of the year, 2018.3, is now available. This update contains the following new features and content changes:

Content updates

Adenosine receptors
Chemokine receptors
Cholecystokinin receptors
Dopamine receptors
Ghrelin receptors
Opioid receptors
GPR55 receptors

MRetinoic acid receptor

Transient Receptor Potential channels
voltage-gated sodium channels

Guanylyl cyclases (GCs)
Janus kinase (JakA) family
Mitogen-activated protein kinases (MAP kinases)
Nitric oxide synthases

Catalytic Receptors:
Natriuretic peptide receptor family

ABCG subfamily
Monoamine transporter subfamily

CD molecules

Anti-malarial data

The existing Antimalarial targets family has been updated with 5 new P. falciparum (3D7) targets:

  • PfATP4 (Plasmodium falciparum ATPase4)
  • PfDHFR-TS (Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase)
  • PfDXR (Plasmodium falciparum 1-deoxy-D-xylulose 5-phosphate reductoisomerase)
  • PfeEF2 (Plasmodium falciparum elongation factor 2)
  • PfPI4K (Plasmodium falciparum phosphatidylinositol 4-kinase)

A new Antimalarial ligands family has been created and contains 30 ligands all tagged as an antimalarial in the database. Of these 30, 20 are new ligands curated for this release.

New website features

GtoImmuPdb now public

The IUPHAR Guide to IMMUNOPHARMACOLOGY is now at its first public release and is no longer considered a beta version. We will continue to develop the portal and specific immuno interfaces as well as continuing curation towards its official launch in October 2018. This will be at the BPS Immunopharmacology: Challenges, opportunities and research tools meeting in Edinburgh, 1st-2nd October 2018.

Disease Summary Pages

The disease summary pages have been modified to improve the payout of target information and provide links to help to understand terms and symbols. The display of associated ligand is now in a sortable table and the comments section includes bioactivity comments where present. We have also include links to the specific clinical data or bio-activity tabs on ligand summary pages.

Posted in Database updates, Guide to Immunopharmacology, Guide to Malaria Pharmacology

Commentary on the distinction between Cannabis and cannabinoids

The Cannabis plant is a natural product from which more than 100 apparently unique metabolites (cannabinoids) have been identified. Many of these have been found in human plasma following consumption of Cannabis preparations. The most well-recognised is tetrahydrocannabinol, THC, because of its well-documented psychotropic effects mediated through activating CB1 cannabinoid receptors. It has been used clinically as an anti-emetic and for treating glaucoma.

Cannabidiol, CBD, is also a prominent metabolite from the plant, which lacks the psychotropic effects of THC, since it is not an agonist at CB1 cannabinoid receptors. It is in advanced trials for treating childhood epilepsy, but may also have benefit in schizophrenia or post-traumatic stress disorder. The molecular mechanisms of action of CBD are not precisely defined, but may involve multiple targets.

A standardised combination of THC and CBD is available in many countries, including the UK as a licensed medicine for treating the symptoms of multiple sclerosis.

There is a lack of clear understanding of the biological effects of the majority of the other cannabinoid metabolites from the plant, which may have applications in inflammatory disorders, nausea and metabolic disorders, such as type II diabetes.

In many countries, Cannabis itself is licensed as a medicine for indications such as pain relief or the weight loss associated with terminal cancer or AIDS. However, preparations from Cannabis are highly variable in terms of the spectrum and concentrations of cannabinoid content, as well as other compounds present in the plant, such as the terpenoids, which have also been proposed to have independent bioactivity.

Commentary by Steve Alexander (@mqzspa) & Anthony Davenport

Posted in Hot Topics, Uncategorized

GtoPdb: Database Status Reports

As some of our contacts may know, we hold hemi-annual meetings between IUPHAR, BPS the GtoPdb team, together with invited guests from our collaborators and NC-IUPHAR committee representatives. Covering ~ 2.5 days these usually take place in Paris or Edinburgh. One of the outputs from these rewarding gatherings is an extensive (i.e. ~ 20-25 pages) database report document. For interested parties these provide a usefully detailed snapshot of what we have collectively been up to for the preceding 6-month period.

The last three of these are now on-line (

The latest one (May 2018) also includes links to slide sets shown in the meeting that accompany the report, which are also available here:

Database Status Report: Core GtoPdb

Database Status Report: GtoImmuPdb

Linking GtoPdb, PubChem and PubMed


Posted in Database updates, Technical, Uncategorized

Hot topic (update): from double to triple whammy for BACE1 inhibitors

19 June 2018 update. Announced only about a week after the events described below,  yet a third clinical candidate, lanabecestat  (AZD-3293, LY3314814) has also bitten the dust (4).  The two PhIII trials were stopped because they were deemed unlikely to meet their primary endpoints. This bad news engendered yet another “In The Pipeline” commentary  If detailed reports are eventually published these will be curated as new references for the ligand entry.


BACE1  (beta secretase 1, BACE-1 or BACE) has been a key target for Alzheimer’s disease (AD) for nearly two decades (1).  However, there was a major disappointment when the Phase III trials with the Merck inhibitor verubecestat failed unequivocally despite lowering A-beta levels.  The termination is reported both in NCT01739348  and the  May 2018  full paper on the trial results (2).  The gravity of this setback is underlined by the “In The Pipeline” commentary title “Merck’s BACE-Inhibitor Alzheimer’s Wipeout” wherein it is suggested that this brings the validation status of this target and, by definition, other inhibitors in late-stage development into doubt.  Thus, even glimmers of success for any mechanistic class of AD  therapy would seem to be currently extinguished.   There remains perhaps the slimmest of hopes from the recent report that the initial process of plaque formation might yet prove sensitive to therapeutic BACE1 inhibition (3).  However, there may be no diagnostic and/or biomarker specific enough to identify prospective asymptomatic patients this early in disease development.

The bad news for BACE1 inhibitors was compounded by a press release from Janssen in the same month. They reported serious liver enzyme elevations for some participants in Janssen’s atabecestat  (JNJ-54861911) Phase 2b/3 trial.  While this may be a chemotype liability for this series rather than a target-related issue, it does mean that yet another AD drug candidate has bitten the dust.  We would hope that a full clinical data report on this trial cessation could be pending,  However,  despite a number of early clinical reports, Janssen has not so far published any primary in vitro medicinal chemistry papers on this compound.  Comments about both these failures have also just  appeared in Nature Reviews in Drug Discovery

N.b. Our BACE1  target entry is in the process of being updated so a number of new inhibitors and curatorial comments will appear in database release 2018.3.  The technicalities of gathering these new structures, including unblinding JNJ-54861911, as well as what might still be progressing,  are described in this blog post.

Comments by Chris Southan (@cdsouthan)

1) Southan and Hancock  (2013) A tale of two drug targets: the evolutionary history of BACE1 and BACE2. Front Genet. Dec 17;4:293. doi: 10.3389/fgene.2013.00293.[PMID 24381583]

2) Egan et. al.  (2018)  Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease. N. Engl. J. Med., 378 (18): 1691-1703, [PMID 29719179]

3) Peters et. al. (2018) BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology, Acta Neuropathol. May;135(5):695-710. doi: 10.1007/s00401-017-1804-9. [PMID 29327084]

4) Update on Phase 3 Clinical Trials of Lanabecestat for Alzheimer’s Disease (2918)  Eli Lilly and AstraZeneca press release [CUL 14602932]

Posted in Hot Topics