Professor Iain McEwan

Professor Iain McEwan
Professor Iain McEwan
Professor Iain McEwan

BSc (Hons), PhD

Personal Chair, Interim Director of Institute of Medical Sciences

Accepting PhDs

About
Email Address
iain.mcewan@abdn.ac.uk
Telephone Number
+44 (0)1224 437328
Office Address
2.62.1 Institute of Medical Sciences
Foresterhill Campus
Ashgrove Road West
AB25 2ZD

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School/Department
School of Medicine, Medical Sciences and Nutrition

Biography

Iain McEwan graduated with a first in Biochemistry from the University of Strathclyde in 1983, and went on to gain a PhD in 1987 from the University of Glasgow.

From 1986-1989 he worked as a Postdoctoral research fellow at the Friedrich Meischer Institute in Basel, Switzerland. He then moved to Sweden where he gained experience working as a Postdoctoral research fellow at the Karolinska Institute, Stockholm and then as a Junior group leader in the Department of Biosciences at Novum, Karolinska Institute, Stockholm, Sweden.

In 1997 he moved south (!) to take up a lectureship at the University of Aberdeen and in 2003 was made a Senior Lecturer, Reader in 2005 and awarded a Personal Chair in 2009.

Research

Research Overview

The research of my group focuses on investigating the molecular mechanisms of action of the human androgen receptor and translating fundametal descoveries to the clinic. The androgen receptor is an intracellular receptor protein that acts as the 'gatekeeper' for the actions of the male steroid hormones testosterone and dehydrotestosterone. The androgen receptor functions as a liganded-activated transcription factor that both up-and down-regulates networks of genes in target tissues. Mutations in the receptor can lead to a disruption of male development (androgen insensitivity) and a neuromuscular degenerative disorder (Kennedy's disease). Mutations have also been identified in patients with prostate cancer both before and after hormone therapy. It has been proposed that such mutations may influence the effectiveness of androgen ablation therapy and play a role in the progression to hormone-refractory disease.

The androgen receptor is organised into discrete structural and functional domains, consisting of a central DNA binding domain (DBD), flanked by a C-terminal ligand binding domain (LBD), and a structurally distinct N-terminal domain (NTD) important for receptor-dependent transactivation. The androgen receptor can regulate both the initiation and elongation steps of the transcription cycle and we have identified and characterised an interaction between the receptor and the general transcription factor TFIIF, which appears important for the transcription initiation steps (see model). We have also shown that the androgen receptor-transactivation domain folds into a more stable conformation, possibly involving alpha-helix formation, resistant to protease attack, in the presence of the target protein TFIIF or the structure stabilising solutes trimethylene N-oxide (TMAO) and trifluorethanol (TFE). Thus our working hypothesis is that the receptor-NTD is structurally flexible, permitting multiple protein-protein interactions with the transcriptional machinery. Specific protein-protein interactions will induce folding of the receptor-transactivation domain and provide a platform for the assembly of a transcriptionally competent complex, containing basal transcription factors and co-activator proteins (SRC, CBP).

Recently, we have extended these studies to investigate the structure-function of the human mineralocorticoid receptor N-terminal domain. The mineralocorticoid receptor is a risk factor in hypertension, cardiovascular disease and metabolic synodrome. This region has a complex transactivation function consisting of different sub-domains which exhibit different functional and/or structural properties. Current work aims to investigate the translational potential of these studies in the treatment of hormone-dependent diseases.

Several potential PhD project opportunities are available:

  • Therapeutic Targeting of the Structurally Plastic N-terminal Domain of Steroid Receptors
  • Tissue-selective regulation and expression of the human androgen receptor gene

Research Areas

Accepting PhDs

I am currently accepting PhDs in Biomedical Sciences.


Please get in touch if you would like to discuss your research ideas further.

Email Me

Biomedical Sciences

Supervising
Accepting PhDs

Research Specialisms

  • Biochemistry
  • Molecular Biology
  • Biomolecular Science
  • Endocrinology

Our research specialisms are based on the Higher Education Classification of Subjects (HECoS) which is HESA open data, published under the Creative Commons Attribution 4.0 International licence.

Current Research

Current research focuses on two main themes:

1. The expression and control of the androgen receptor gene in male and female tissues, including prostate, bladder and bone. We are also investigating the role of steroid hormones action on immune cell function in health and cancer. These projects are in collaboration with Professor Heather Wilson (IMS https://www.abdn.ac.uk/ims/research/profiles/h.m.wilson) and Professor Philippa Saunders and Dr Douglas Gibson University of Edinburgh.

2. Developing novel therapeutic strategies to switch off androgen receptor function in cancer cells. These projects involve medicinal chemistry approaches to synthesising bespoke small molecule inhibitors and novel biologics called SoloMERs in collaboration with the biopharmaceutical company Elasmogen (https://www.elasmogen.com/about-elasmogen/).

 

Collaborations

My group collaborates with a number of colleagues in both nationally (UK) and internationally (The Netherlands, Spain and North America). Current interdisplenary collaborative projects focus on mathematical modelling of gene expression and medicinal chemistry. We also have a collaboration with a local biopharmacetical company, called Elasmogen invetigating biologics as novel therapeutics in hormone-dependent cancers. 

Supervision

My current supervision areas are: Biomedical Sciences.

I have successfully supervised more than 10 PhD students since joining the UNiversity of Aberdeen. I am currently supervising four students: two in their first year; one second year; and one in the final year.

Funding and Grants

Research in my laboratory is currently supported by:

Projects grants from the Prostate Cancer Research Centre (https://www.prostate-cancer-research.org.uk/), the Medical Research Council (DPFS award) (https://mrc.ukri.org/) and Pilot STudy Award from Friends of Anchor (https://www.friendsofanchor.org/).

PhD studentship awards from Cranes (https://www.cranes.org.uk/), EASTBIO-BBSRC (http://www.eastscotbiodtp.ac.uk/) and Aberdeen Cancer PhD programme (https://www.abdn.ac.uk/smmsn/research/biobank-1025.php).

Teaching

Teaching Responsibilities

I am course coordinator for Honours Biochemistry Option 1 (BC4014).

Non-course Teaching Responsibilities

Personal Tutor

Publications

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  • Nuclear Receptors: One Big Family

    McEwan, I. J.
    The Nuclear Receptor Superfamily: Methods and Protocols. Humana Press, pp. 3-18, 16 pages
    Chapters in Books, Reports and Conference Proceedings: Chapters
  • Using intrinsic fluorescence emission spectroscopy to study steroid receptor and coactivator protein conformation dynamics

    Watt, K., McEwan, I. J.
    The Nuclear Receptor Superfamily: Methods and Protocols. McEwan, I. J. (ed.). Humana Press, pp. 205-218, 14 pages
    Chapters in Books, Reports and Conference Proceedings: Chapters
  • Consequences of poly-glutamine repeat length for the conformation and folding of the androgen receptor amino-terminal domain

    Davies, P., Watt, K., Kelly, S. M., Clark, C., Price, N. C., McEwan, I. J.
    Journal of Molecular Endocrinology, vol. 41, no. 5, pp. 301-314
    Contributions to Journals: Articles
  • Functional Characterisation of the Native NH2- Terminal Transactivation Domain of the Human Androgen Receptor: Binding Kinetics for Interactions with TFIIF and SRC-1a

    Lavery, D. N., McEwan, I. J.
    Biochemistry, vol. 47, no. 11, pp. 3352-3359
    Contributions to Journals: Articles
  • Structural characterization of the native NH2-terminal transactivation domain of the human androgen receptor: a collapsed disordered conformation underlies structural plasticity and protein-induced folding

    Lavery, D. N., McEwan, I. J.
    Biochemistry, vol. 47, no. 11, pp. 3360-3369
    Contributions to Journals: Articles
  • The Nuclear Receptor Superfamily Methods and Protocols

    McEwan, I. J.
    Methods in Molecular Biology, vol. 550
    Contributions to Journals: Reviews of Books, Films and Articles
  • The human androgen receptor AF1 transactivation domain: interactions with transcription factor IIF and molten-globule-like structural characteristics

    Lavery, D. N., McEwan, I. J.
    Biochemical Society Transactions, vol. 34, pp. 1054-1057
    Contributions to Journals: Articles
  • Structural dynamics of the human androgen receptor: implications for prostate cancer and neurodegenerative disease

    Duff, J., Davies, P., Watt, K., McEwan, I. J.
    Biochemical Society Transactions, vol. 34, pp. 1098-1102
    Contributions to Journals: Articles
  • Induced alpha-Helix Structure in the Aryl Hydrocarbon Receptor Transactivation Domain Modulates Protein-Protein Interactions

    Watt, K., Jess, T. J., Kelly, S. M., Price, N. C., McEwan, I. J.
    Biochemistry, vol. 44, pp. 734-743
    Contributions to Journals: Articles
  • Intra-domain Communication Between the N-Terminal and DNA-binding Domains of the Androgen Receptor: Modulation of Androgen Response Element DNA Binding.

    Brodie, J., McEwan, I. J.
    Journal of Molecular Endocrinology, vol. 34, pp. 603-615
    Contributions to Journals: Articles
  • Mutation of Histidine 874 in the Androgen Receptor Ligand Binding Domain Leads to Promiscuous Ligand Activation and Altered p160 Coactivator Interactions

    Duff, J., McEwan, I. J.
    Molecular Endocrinology, vol. 19, pp. 2943-2954
    Contributions to Journals: Articles
  • Structure and Function of Steroid Receptor AF1 Transactivation Domains: Induction of Active Conformations

    Lavery, D., McEwan, I. J.
    Biochemical Journal, vol. 389, pp. 449-464
    Contributions to Journals: Articles
  • In Vitro regulation of reporter gene transcription by the androgen receptor AF1 domain

    Choudhry, M. A., McEwan, I. J.
    Biochemical Society Transactions, vol. 32, pp. 1103-1106
    Contributions to Journals: Articles
  • Induced alpha-helix Structure in AF1 of the Androgen Receptor Upon Binding Transcription Fcator TFIIF

    Kumar, R., Betney, R., Li, J., Thompson, E. B., McEwan, I. J.
    Biochemistry, vol. 43, no. 11, pp. 3008-3013
    Contributions to Journals: Articles
  • Molecular mechanisms of androgen receptor-mediated gene regulation: structure-function analysis of the AF-1 domain

    McEwan, I. J.
    ENDOCRINE-RELATED CANCER, vol. 11, no. 2, pp. 281-293
    Contributions to Journals: Articles
  • Sex, drugs and gene expression: signalling by members of the nuclear receptor superfamily

    McEwan, I. J.
    Essays in Biochemistry
    Contributions to Journals: Review articles
  • The nuclear receptor superfamily: Preface

    McEwan, I. J.
    Essays in Biochemistry, vol. 40, pp. xi-xii
    Contributions to Journals: Editorials
  • Role of conserved hydrophobic amino acids in androgen receptor AF-1 function

    Betney, R., McEwan, I. J.
    Journal of Molecular Endocrinology, vol. 31, no. 3, pp. 427-439
    Contributions to Journals: Articles
  • The androgen receptor transactivation domain: the interplay between protein conformation and protein-protein interactions

    Reid, J. E., Betney, R., Watt, K., McEwan, I. J.
    Biochemical Society Transactions, vol. 31, no. Pt 5, pp. 1042-1046
    Contributions to Journals: Articles
  • The androgen receptor interacts with multiple regions of the large subunit of general transcription factor TFIIF

    Reid, J., Murray, I., Watt, K., Betney, R., McEwan, I. J.
    The Journal of Biological Chemistry, vol. 277, no. 43, pp. 41247-41253
    Contributions to Journals: Articles
  • Conformational analysis of the androgen receptor amino-terminal domain involved in transactivation. Influence of structure-stabilizing solutes and protein-protein interactions

    Reid, J., Kelly, S. M., Watt, K., Price, N. C., McEwan, I. J.
    The Journal of Biological Chemistry, vol. 277, no. 22, pp. 20079-20086
    Contributions to Journals: Articles
  • Bakers yeast rises to the challenge: reconstitution of mammalian steroid receptor signalling in S. cerevisiae

    McEwan, I. J.
    Trends in Genetics, vol. 17, no. 5, pp. 239-243
    Contributions to Journals: Articles
  • Structural and functional alterations in the androgen receptor in spinal bulbar muscular atrophy

    McEwan, I. J.
    Biochemical Society Transactions, vol. 29, no. Pt 2, pp. 222-227
    Contributions to Journals: Articles
  • Gene regulation through chromatin remodelling by members of the nuclear receptor superfamily

    McEwan, I. J.
    Biochemical Society Transactions, vol. 28, pp. 369-373
    Contributions to Journals: Articles
  • The nuclear-receptor interacting protein (RIP) 140 binds to the human glucocorticoid receptor and modulates hormone-dependent transactivation

    Windahl, S. H., Treuter, E., Ford, J., Zilliacus, J., Gustafsson, J. A., McEwan, I. J.
    The Journal of Steroid Biochemistry and Molecular Biology, vol. 71, no. 3-4, pp. 93-102
    Contributions to Journals: Articles
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