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A TPX2 Proteomimetic Has Enhanced Affinity for Aurora-A Due to Hydrocarbon Stapling of a Helix

DOI: 10.1021/acschembio.6b00727 DOI Help

Authors: Yana K. Rennie (University of Leicester) , Patrick Mcintyre (University of Leicester) , Tito Akindele (University of Leicester) , Richard Bayliss (University of Leicester; University of Leeds) , Andrew G. Jamieson (University of Glasgow)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 11 , PAGES 3383 - 3390

State: Published (Approved)
Published: December 2016
Diamond Proposal Number(s): 10369

Open Access Open Access

Abstract: Inhibition of protein kinases using ATP-competitive compounds is an important strategy in drug discovery. In contrast, the allosteric regulation of kinases through the disruption of protein–protein interactions has not been widely adopted, despite the potential for selective targeting. Aurora-A kinase regulates mitotic entry and mitotic spindle assembly and is a promising target for anticancer therapy. The microtubule-associated protein TPX2 activates Aurora-A through binding to two sites. Aurora-A recognition is mediated by two motifs within the first 43 residues of TPX2, connected by a flexible linker. To characterize the contributions of these three structural elements, we prepared a series of TPX2 proteomimetics and investigated their binding affinity for Aurora-A using isothermal titration calorimetry. A novel stapled TPX2 peptide was developed that has improved binding affinity for Aurora-A and mimics the function of TPX2 in activating Aurora-A’s autophosphorylation. We conclude that the helical region of TPX2 folds upon binding Aurora-A, and that stabilization of this helix does not compromise Aurora-A activation. This study demonstrates that the preparation of these proteomimetics using modern synthesis methods is feasible and their biochemical evaluation demonstrates the power of proteomimetics as tool compounds for investigating PPIs involving intrinsically disordered regions of proteins.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-Macromolecular Crystallography