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Optimization and development of functionally active anti-Cdc42/Ras peptides

  • Full or part time
    Dr Darerca Owen
  • Application Deadline
    Friday, December 16, 2016
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

A fully funded 4-year BBSRC-DTP Industrial CASE PhD studentship is available, commencing in October 2017, to develop peptide-based therapeutics designed to target Ras-driven cancers. The project builds on a considerable body of data generated in the academic research group led by Drs Darerca Owen and Helen Mott investigating the structure, thermodynamics and functions of small G protein-effector complexes, which has led to the development of candidate peptide therapeutics. The aim of the BBSRC-DTP Industry CASE awards is to provide PhD students with a first class, challenging training experience within the context of a mutually beneficial collaboration between academic and non-academic partner organizations. This project is partnered by MedImmune, a world-leading company specializing in antibody and peptide therapeutics, based just outside Cambridge. The work will use MedImmune’s considerable experience to optimize peptides for use as cellular probes and as lead therapeutic molecules. Candidate peptides will be tested in the Owen/Mott laboratory using a range of biophysical and biochemical assays. Those peptides with desired properties will be taken into cell-based assays to test their effects on Ras signalling. The project will provide a thorough training in a wide range of state-of-the-art techniques: advanced peptide chemistry and high-throughput screening techniques; molecular biology, protein biochemistry, biophysics and NMR for protein-protein interaction analysis; cell culture assays e.g. cell proliferation, anchorage-independent growth and focus formation assays.

The successful candidate will join the group led by Drs Darerca Owen and Helen Mott (http://www.bio.cam.ac.uk/~hrm28/) in the Department of Biochemistry, University of Cambridge and will be part of the Antibody Discovery and Protein Engineering (ADPE) department at MedImmune, working alongside a skilled team of scientists in a dynamic biotech environment, supervised by Dr Jeff Revell (https://www.medimmune.com/).


Funding Notes

Applicants should hold or be about to achieve a First/Upper-Second (2.i) class degree in a relevant subject. BBSRC studentships are available to UK nationals/EU students who meet UK residency requirements (see View Website)

The successful candidate will receive a stipend at RCUK rates for 4 years (£14,296 per annum for 2016-17) and in addition will benefit from a £2,500 per annum stipend enhancement; fees will be met in full.

Applications to Dr Darerca Owen () by 16th December 2016, enclosing a cover letter, a detailed curriculum vitae and the names and contact details of two academic referees.


References

Rittinger, K. et al.(1997) Crystal Structure of a small G protein in complex with the GTPase-activating protein RhoGAP. Nature 388:693

Mott, H.R., et al.(1999) Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK Tyrosine Kinase. Nature 399:384.

Morreale, A. et al.(2000) Structure of Cdc42 complexed with the GTPase binding domain of PAK. Nat.Struct.Biol. 7:384

Mott, H.R. et al.(2003) Structure of the GTPase-Binding domain of Sec5 and Investigation of its Ral-binding Site J.Biol.Chem 278:17053

Owen, D. et al.(2003) Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and Protein Kinase C Related Kinase 1 (PRK1) J.Biol.Chem. 278:50578

Elliot-Smith, A.E. et al.(2005) Specificity Determinants on Cdc42 for binding its effector protein ACK Biochemistry 44:12373

Elliot-Smith, A.E. et al.(2007) Double mutant cycle thermodynamic analysis of the hydrophobic Cdc42-ACK protein:protein interaction Biochemistry 46:14087

Modha, R. et al.(2008) The Rac1 Polybasic Region Is Required for Interaction with Its Effector PRK1 J.Biol.Chem. 283:1492

Owen, D. et al.(2008) The IQGAP1-Rac1 and IQGAP1-Cdc42 Interactions: Interfaces differ between the complexes J.Biol.Chem. 283:1692

Mott, H.R. and Owen, D.(2009) 'Structure of Rho Family Targets' Handbook of Cell Signalling 2:1827

Fenwick, R.B. et al.(2010) The RalB-RLIP76/RalBP1 complex reveals a novel mode of Ral-effector interaction. Structure 18:985

Hutchinson, C.L. et al.(2011) Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1. Biochemistry 50:2860

Rajasekar, K.V. et al.(2013) The structure of the RLIP76 (RalBP1) RhoGAP domain-Ral binding domain dyad: fixed position of the domains leads to dual engagement of small G proteins at the membrane. Structure 21:2131

Hutchinson, C.L. et al.(2013) Differential binding of RhoA, B and C to the PRK isoforms PRK1, 2 and 3: PRKs have highest affinity for RhoB. Biochemistry 52:7999

Mott, H.R.&Owen, D.(2014) Structure and Function of RLIP76 (RalBP1): an intersection point between Ras and Rho signalling. Biochemical Society Transactions 42:52

Campbell, L. et al.(2015) Thermodynamic mapping of effector protein interfaces with RalA and RalB. Biochemistry 54:1380

Mott, H.R.&Owen, D.(2015) Ras superfamily Effector Complexes: What have we learned in two decades? Critical Reviews in Biochemistry and Molecular Biology 50:85

Watson, J.R. et al.(2016) Investigation of the Interaction Between Cdc42 and its Effector TOCA1: Handover of Cdc42 to the Actin Regulator N-WASP is Facilitated by Differential Binding Affinities. J. Biol. Chem. 291:13875

Thomas, J.T. et al.(2016) Inhibition of Ral GTPases using a stapled peptide approach. J. Biol. Chem. 291:18310






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