Molecular and structural studies on insulin: Insulin Receptor interactions
Insulin – Insulin Receptor (IR) interactions are at the centre of insulin-driven control of human metabolism, and – to some extent – growth and life-span regulation as well. Disruption of insulin secretion, actions, or both, leads to severe metabolic syndrome of which diabetes type 1 (insulin-dependent) and type 2 (non-insulin dependent) are the main manifestations. High similarity of insulin to Insulin-like Growth Factors (IGF-I and II) and IR to IGF-1R results in some overlaps of insulin’s metabolic and IGFs’ mitogenic signaling pathways. Furthermore, the occurrence of two isoforms of IR (IR-A: implicated in both metabolic and in mitogenic signaling, and IR-B of purely metabolic function), and their hetero-dimerisation (including IGF-1R) expands the complexity of this hormonal system.
Therefore a detailed 3-D description of insulin:IR coupling is paramount for understanding IR-mediated signal transduction and initiation of insulin signaling. The first insight into the effective insulin:IR molecular engagement was achieved, but formidable challenges of production of IR fragments and low resolution of insulin:IR complexes slow down further progress in this field.
The main aims of this project are: (a) search for workable insulin:IR molecular platform by design, optimization and efficient scale up of production of various fragments of IR ectodomain for structural work, (b) expansion of current low-resolution (~3-4 Å) X-ray structural studies of insulin-IR complexes towards detail atomic definition of insulin:IR interface, and, ultimately, elucidation of the molecular bases of the complete engagement of insulin with IR.
The project is sponsored by Novo Nordisk (Copenhagen), and is run in York in collaboration with their laboratories. The student will have access to a unique know-how and in-house methodologies of Novo Nordisk. This project is for 4 years starting as early as possible in 2016 up to the 1st October 2016.
Shortlisting will take place as soon as possible after the closing date and successful applicants will be notified promptly. Shortlisted applicants will be invited for an interview with Professor Brzozowski following the closing date.
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This project is fully funded for 4 years by the Guy Dodson Fund for Structural Biology research at York, established in 2013 with a donation from Danish pharmaceutical company, Novo Nordisk. Funding will cover (i) tuition fees at the UK/EU rate, (ii) a tax-free annual stipend at the standard Research Council rate (£14,057 for 2015-2016, typically increases annually in line with inflation) and (iii) a contribution towards research costs. Applications are welcomed from those from the UK and other EU countries.
Menting et al. How insulin engages its primary binding site on the insulin receptor. (2013) Nature, 493, 241-245
Jiracek et al. Implications for the active form of human insulin based on structural convergence of highly active hormone analogues. (2010) PNAS, 107, 1966-1970
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FTE Category A staff submitted: 47.06
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