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(BBSRC DTP CASE) Mapping the role of allostery in the conformation of proteins using hybrid mass spectrometry approaches

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  • Full or part time
    Prof P Barran
    Prof A Munro
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

We have developed a suite of hybrid mass spectrometry approaches to determine absolute conformational change along with conformational rearrangement in proteins and protein complexes (Beveridge, Leys & Barran, Nature Commun. 2016, 7, 12163, Pacholarz, Barran Structure 2017 online, Pacholarz, Barran Angew. Chemie. Int. Ed. 2014 53 (30), 7765-7769,). This project will apply these methods to study proteins that form part of drug discovery programs at Astra Zeneca. Work to be performed will include direct measurement of shape and size in the gas phase via the coupling of nano electrospray ionisation with ion mobility mass spectrometry to provide experimental collision cross sections (CCS) along with stoichiometric information. We also develop chip based hydrogen deuterium exchange (HDX) in solution using mass spectrometry (MS) as the detector to discern alterations in protein conformations in solution at the peptide level. We have developed an empirical framework along a toy model that considers the conformational landscape available to monomeric proteins in the gas phase allowing more conformationally dynamic systems to be distinguished from those more natively structured (Beveridge Barran Anal. Chem. 2015 86 (22), 10979-10991). Experimental findings will be referenced to structures obtained with other methods and computational approaches used to facilitate the comparison.

Qualification
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Contact for further Information
For more details contact Professor Perdita Barran ([email protected])

www.mbc.manchester.ac.uk

Funding Notes

This is a CASE studentship is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships

References

1. Stengel, F.; Aebersold, R.; Robinson, C. V., Joining Forces: Integrating Proteomics and Cross-linking with the Mass Spectrometry of Intact Complexes. Mol Cell Proteomics 2012, 11 (3).

2. Jurneczko, E.; Cruickshank, F.; Porrini, M.; Clarke, D. J.; Campuzano, I. D. G.; Morris, M.; Nikolova, P. V.;Barran, P. E., Probing the Conformational Diversity of Cancer-Associated Mutations in p53 with Ion-Mobility Mass Spectrometry. Angew Chem Int Edit 2013, 52 (16), 4370-4374.

3. Bellina, B.; Brown, J. M.; Ujma, J.; Murray, P.; Giles, K.; Morris, M.; Compagnon, I.; Barran, P. E., UV photodissociation of trapped ions following ion mobility separation in a Q-ToF mass spectrometer. Analyst 2014, 139 (24), 6348-6351.

4. Kutta, R. J.; Hardman, S. J. O.; Johannissen, L. O.; Bellina, B.; Messiha, H. L.; Ortiz-Guerrero, J. M.; Elias-Arnanz, M.; Padmanabhan, S.; Barran, P.; Scrutton, N. S.; Jones, A. R., The photochemical mechanism of a B-12-dependent photoreceptor protein. Nature Communications 2015, 6.

5. Payne, K. A. P.; Fisher, K.; Sjuts, H.; Dunstan, M. S.; Bellina, B.; Johannissen, L.; Barran, P.; Hay, S.;Rigby, S. E. J.; Leys, D., Epoxyqueuosine Reductase Structure Suggests a Mechanism for Cobalamin-dependent tRNA Modification. Journal of Biological Chemistry 2015, 290 (46), 27572-27581.

6. Beveridge, R.; Migas, L. G.; Payne, K. A. P.; Scrutton, N. S.; Leys, D.; Barran, P. E., Mass spectrometry locates local and allosteric conformational changes that occur on cofactor binding. Nat Commun 2016, 7.

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