About the Project
Our work addresses the relationship between structure and function in small G proteins and their effector complexes along with their role in cellular signaling cascades. We have determined several structures (by NMR) of small G proteins (primarily of the Rho and Ras families) in complex with the G protein binding regions of their effector proteins. Our structures facilitated the design of mutations that selectively inhibited the interaction of Cdc42 with its effectors. Thermodynamic analysis of these mutants led to the identification of ’hotspots’ on the G protein surface that define areas which could be targeted for therapeutic purposes. We are now using this information to generate lead therapeutic peptides. We also have a major programme of work currently underway to delineate the role of the Cdc42 effector and tyrosine kinase, ACK, in tumourigenesis.
MRC-DTP and BBSRC_DTP studentships are available to eligible students (UK nationals and EU students who meet the UK residency requirements).
Biochemistry Departmental AstraZeneca studentships are also available to UK/EU nationals View Website
CRUK Cambridge Centre studentships are available to UK/EU students and international students through the Cellular and molecular biology programme View Website
Applicants with full funding from a competitive source of any nationality will also be considered
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. and 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 and 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
Watson, J.R. et al. (2016) Cdc42 in actin dynamics: An ordered pathway governed by complex equilibria and directional effector handover. Small GTPases 7:1
Tetley, G.J.N. et al. (2017) A dock and coalesce mechanism driven by hydrophobic interactions governs Cdc42 binding with its effector protein ACK. J. Biol. Chem. 292: 11361
Mott, H.R. and Owen D. (2018) Bioblockades join the assault on small G protein signaling. Seminars in Cancer Biology (doi.org/10.1016/j.semcancer.2018.01.001)
Owen D. and Mott, H.R. (2018) CRIB effector disorder: exquisite function from chaos. Biochemical Society Transactions 46: 1289
Tetley, G.J.N. et al. (2018) Bond swapping from a charge cloud allows flexible co-ordination of upstream signals through WASP: Multiple regulatory roles for the WASP basic region. J. Biol. Chem. 293: 15136
Mott, H.R. and Owen D. (2018) Allostery and dynamics in small G proteins. Biochemical Society Transactions 46: 1333
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