Mechanism-based design and screening for synthetic inhibitors targeting the small GTPase splice variant RAC1B

Details

RAC1 is a small GTPase protein that functions as a key signaling node downstream of various microenvironmental signaling pathways. RAC1B, a RAC1 variant with an extra19 amino acid insert, is overexpressed in various cancers, including breast, colorectal and lung cancers [1]. This project will seek to unravel the differences in signalling mechanism of RAC1 and RAC1B leveraging structural biology, high-throughput 19F NMR, advanced molecular simulation, combined with the design, synthesis and biophysical evaluation of small chemical tool compounds that bind tightly and selectively to RAC1B over RAC1. Thus, this interdisciplinary project combines computational, chemical and biophysical aspects to offer an exciting research opportunity at the experimental medicine and enzymology interface.

[1] Chen F., et al. RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells. Oncogene, (2023), doi:10.1038/s41388-022-02574-6

Entry Requirements

Applicants should hold (or be about to obtain) a First or Upper Second class (2:1) UK honours degree, or international equivalent, in a relevant subject.

Application Guidance

Candidates must contact the primary supervisor before applying to discuss their interest in the project and assess their suitability.

Apply directly via this link:

https://tinyurl.com/m87wpezv

or on the online application portal, select “PhD Structural Biology” Programme as the programme of study.

Please ensure that your application includes all required supporting documents:

· Curriculum Vitae (CV)

· Supporting Statement

· Academic Certificates and Transcripts

Equality, diversity and inclusion are central to the University’s activities. The full statement can be found here: https://www.bmh.manchester.ac.uk/study/research/getting-started/equality-diversity-inclusion/

Funding Notes

This 4 year PhD project is for self funded students.

At Manchester we offer a range of scholarships, studentships and awards at university, faculty and department level, to support both UK and overseas postgraduate researchers applying for competition and self-funded projects.

For more information, visit our funding page or search our funding database for specific scholarships, studentships and awards you may be eligible for.

References

1. P. Baumann, Y. Jin*. Far-reaching effects of tyrosine64 phosphorylation on Ras revealed with BeF3- complexes. Comm. Chem. (2024) 7, 19.

2. E. Pellegrini, P. Juyoux, J. von Velsen, N. Baxter, Y. Jin, H. Dannatt, M. Cliff, J. Waltho, M. W. Bowler. Metal fluorides – multi-functional tools for the study of phosphoryl transfer enzymes. Structure (2024), 32, 1–13

3. Q. Zhou, P. Catalan, H. Bell, P. Baumann, R. Evans, J. Yang, Z. Zhang, D. Zappala, Y. Zhang, G. M. Blackburn, Y. He*, Y. Jin*. An ion-pair induced intermediate complex captured in Class D carbapenemase reveals chloride ion as a Janus effector modulating activity. ACS. Cent. Sci. (2023), 9, 2339–2349.

4. S. El-Sayed, S. Freeman and R. A. Bryce*. Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation. Protein Sci. (2022) 31, e4420.

5. M. A. Elhemely, A. A. Belgath, S. El-Sayed, K. K. Burusco, M. Kadirvel, A. Tirella, K. Finegan, R. A. Bryce*, I. J. Stratford, and S. Freeman. SAR of novel 3-arylisoquinolinones: meta-substitution on the aryl ring dramatically enhances antiproliferative activity through binding to microtubules. J. Med. Chem. (2022) 65, 4783-4797.