Flexibility and small pockets at protein-protein interfaces: New insights into druggability.

The transient assembly of multiprotein complexes mediates many aspects of cell regulation and signalling in living organisms. Modulation of the formation of these complexes through targeting protein-protein interfaces can offer greater selectivity than the inhibition of protein kinases, proteases or other post-translational regulatory enzymes using substrate, co-factor or transition state mimetics. However, capitalising on protein-protein interaction interfaces as drug targets has been hindered by the nature of interfaces that tend to offer binding sites lacking the well-defined large cavities of classical drug targets. In this review we posit that interfaces formed by concerted folding and binding (disorder-to-order transitions on binding) of one partner and other examples of interfaces where a protein partner is bound through a continuous epitope from a surface-exposed helix, flexible loop or chain extension may be more tractable for the development of "orthosteric", competitive chemical modulators; these interfaces tend to offer small-volume but deep pockets and/or larger grooves that may be bound tightly by small chemical entities. We discuss examples of such protein-protein interaction interfaces for which successful chemical modulators are being developed.We thank our colleagues Alicia Higueruelo, Douglas Pires, Bernardo Ochoa and Chris Radoux for helpful comments and discussions. D.B.A is the recipient of a C. J. Martin Research Fellowship from the National Health and Medical Research Council of Australia (APP1072476). H.J. is supported by a CASE Studentship from the UCB and the Biotechnology and Biological Sciences Research Council (BBSRC) (Grant: BB/J500574/1). T.L.B. receives funding from University of Cambridge and The Wellcome Trust for facilities and support.This is the accepted manuscript of a paper published in Progress in Biophysics and Molecular Biology (Jubb H, Blundell TL, Ascher DB, Progress in Biophysics and Molecular Biology 2015, doi:10.1016/j.pbiomolbio.2015.01.009). The final version is available at http://dx.doi.org/10.1016/j.pbiomolbio.2015.01.009

Actor Network Theory and Sensing Governance: From Causation to Correlation

This article is organised in four sections. The first section introduces sensing governance in terms of the governance of effects rather than causation, focusing on the work of Bruno Latour in establishing the problematic of contingent interaction, rather than causal depth, as key to emergent effects, which can be unexpected and catastrophic. The second section considers in more depth how sensing governance enables politics by other means through putting greater emphasis on relations of interaction, rather than on ontologies of being, and links the methodological approach of sensing governance closely to actor network assumptions that disavow structures of causation. The final two sections analyse how correlation works to reveal new agencies and processes of emergence and how new technologies have been deployed in this area, providing some examples of how the shift from causal relations to sensing effects has begun to alter governmental approaches

Collagen-Based Biomimetic Systems to Study the Biophysical Tumour Microenvironment

The extracellular matrix (ECM) is a pericellular network of proteins and other molecules that provides mechanical support to organs and tissues. ECM biophysical properties such as topography, elasticity and porosity strongly influence cell proliferation, differentiation and migration. The cell’s perception of the biophysical microenvironment (mechanosensing) leads to altered gene expression or contractility status (mechanotransduction). Mechanosensing and mechanotransduction have profound implications in both tissue homeostasis and cancer. Many solid tumours are surrounded by a dense and aberrant ECM that disturbs normal cell functions and makes certain areas of the tumour inaccessible to therapeutic drugs. Understanding the cell-ECM interplay may therefore lead to novel and more effective therapies. Controllable and reproducible cell culturing systems mimicking the ECM enable detailed investigation of mechanosensing and mechanotransduction pathways. Here, we discuss ECM biomimetic systems. Mainly focusing on collagen, we compare and contrast structural and molecular complexity as well as biophysical properties of simple 2D substrates, 3D fibrillar collagen gels, cell-derived matrices and complex decellularized organs. Finally, we emphasize how the integration of advanced methodologies and computational methods with collagen-based biomimetics will improve the design of novel therapies aimed at targeting the biophysical and mechanical features of the tumour ECM to increase therapy efficacy