Previous Seminars: 2011

Click here for details of forthcoming seminars.

Date Speaker(s) Organisation Topic
Previous Seminars 2011

8 Dec 2011

Sarah Cartmell

Manchester University

Perfusion Bioreactors for Bone Tissue Engineering

10 Nov 2011

Chris Hawes

Oxford Brookes

Shaping the endomembrane system

12 Oct 2011

John Runions

Oxford Brookes

Bioimaging demonstrates constraints to protein lateral diffusion in the plant cell plasma membrane

7 Oct 2011

David Scott

National Centre for Macromolecular Hydrodynamics, University of Nottingham

What do I have in solution? Analytical Ultracentrifugation for solving problems of biomolecular characterisation and aggregation

11 Aug 2011

Robert Freedman

Warwick University

Conformations, dynamics and substrate interactions of protein disulphide-isomerase: trying to understand how chemical and conformational processes are coupled in oxidative protein folding

Abstract

Protein disulphide-isomerase (PDI) was one of the first factors identified as playing a part in facilitating protein folding in the cell. It operates in the secretory pathway and is essential for the formation of the correct disulphide bonds in all classes of secreted and cell-surface proteins e.g. antibodies, hormones, cytokines, receptors, digestive enzymes. PDI can be viewed both as an enzyme and as a molecular chaperone in that it facilitates both chemical and conformational change. We want to find out how it works! Its active-site and overall organization are well-understood, but we do not yet have real information on PDI’s range of conformations, its dynamics and how it interacts with its substrates. The seminar will present ongoing work in this area including simulations and experimental studies with NMR, FRET etc.

14 Jul 2011

Richard Treisman

London Research Institute, Cancer Research UK

The MRTFs: linking the actin cytoskeleton to transcriptional regulation

Abstract

The SRF transcription factor controls growth factor-inducible "immediate-early" genes, many genes structural and regulatory components of the actin cytoskeleton, and a large number of muscle-specific genes. Transcription of these targets is linked to extracellular stimuli through two families of signal-regulated SRF coactivator proteins, the Ras-controlled TCFs (ternary complex factors) and the Rho-controlled MRTFs (myocardin related transcription factors), which interact with its DNA-domain in a mutually exclusive fashion. The MRTFs (MAL/MRTF-A and MKL2/MRTF-B) are novel G-actin-binding proteins. They connect the dynamics of the actin cytoskeleton to transcriptional regulation through the so-called Rho-actin signal pathwaywhich, is required for adhesion, spreading, motility and invasiveness in many cell types. G-actin functions directly as a signalling molecule in the Rho-actin signal pathway, through its interaction with the MRTF N-terminal "RPEL" domain, which functions as a G-actin sensor. Signal-induced alterations in actin dynamics affect the interaction of the RPEL domain with G-actin, which inhibits MRTF nuclear import, promotes nuclear export, and inhibits MRTF-dependent transcriptional activation. I will discuss recent studies on the roles of SRF coactivator proteins in vivo, and the molecular mechanisms by which MRTF activity is regulated by G-actin.

9 June 2011

Mark Whittaker

Senior Vice-President in Drug Discovery, Evotec

Fragment based drug discovery: A medicinal chemist’s perspective

Abstract

Fragment-based drug discovery (FBDD) has become an established technique for lead generation within the pharmaceutical and biotech industries. The approach consists of initially screening a library of lower molecular weight molecules (or fragments) using a sensitive assay method and then obtaining structural insights into the interaction of the identified weakly active fragment hits with the biological target to guide medicinal chemistry optimisation. The most robust fragment hit-finding techniques employ an orthogonal assay format for hit confirmation: in such an approach fragments are screened either by a biochemical screen with subsequent hit confirmation using a biophysical technique (e.g. nuclear magnetic resonance [NMR] or surface plasma resonance [SPR]), or vice versa. X-ray crystallography is the method of choice for gaining structural insights into the interaction of fragments with the biological target, and this then leads into medicinal chemistry optimisation utilising the techniques of computationally driven structure-based design. In this seminar an overview of the fragment approach to drug discovery will be given from a medicinal chemist’s perspective and will be illustrated with a case study of a FBDD programme to discover and optimise inhibitors of Heat shock protein 90 (Hsp90) as potential anti-cancer agents..

12 May 2011

Achilles Kapanidis

Physics, Oxford University

Green fingers, red thumb: single-molecule conformational analysis of DNA polymerase

Abstract

Single-molecule methods have uncovered the presence of static and dynamic heterogeneity in many biomolecular systems. We use single-molecule Förster resonance energy transfer (FRET) with alternating-laser excitation (ALEX) to study the conformational dynamics of DNA polymerase and derivatives thereof with decreased fidelity for DNA synthesis. In the latter work, we show that “mutator” DNA polymerases are associated with inefficient full-closing of the fingers subdomain of DNA polymerase in the presence of complementary nucleotides; instead, mutator polymerases populate novel intermediates likely to correspond to partially closed states. Ongoing experiments to capture the real-time conformational and translocational dynamics of DNA polymerase on template DNA will be discussed. I will also discuss switchable-FRET, a new single-molecule FRET method that allows measurements of multiple distances (along with dynamical information) within a single molecule by combining FRET with acceptor photoswitching. Further extensions of switchable FRET should allow monitoring of polymerase dynamics from multiple perspectives.

14 Apr 2011

Robert Ford

Manchester University

Structural biology of capsule assembly in gram-negative bacteria

Abstract

We have studied the structures of membrane proteins involved in the assembly of the polysaccharide capsule of gram negative bacteria. This capsule provides a physical barrier against a variety of threats and is associated with bacterial pathogenicity. Hence components of the capsule assembly pathway have potential as novel antibiotic targets. We have studied various proteins in the assembly pathway using a combination of electron microscopy, X-ray crystallography and molecular modelling. I will describe the structures of the Wza, Wzc and Wzz proteins, all of which contain coiled-coil components and form intriguing oligomeric complexes. The outer membrane-embedded Wza complex appears to act as a gated channel through which polysaccharide passes to the extracellular surface. The Wzz protein determines polysaccharide chain length during polymerisation at the periplasmic surface of the inner membrane, giving rise to various hypotheses ('molecular ruler' or 'molecular stopwatch') about Wzz structure-function relationships. The inner membrane-embedded Wzc complex has autokinase activity which appears to regulate polysaccharide export and may form a bridge spanning the periplasm with the Wza complex. In the course of this lecture, I will argue that studies of the lipid-reconstituted system are essential for structure-function insights of membrane proteins.

10 Mar 2011

Prof Sheena Radford

Institute of Molecular & Cellular Biology, University of Leeds

The challenges and opportunities of understanding protein folding and protein misfolding in health and disease

Abstract

Most proteins fold efficiently to their native structures in vivo, assisted by molecular chaperones. It is now widely known, however, that proteins do misfold and that misfolding events can result in conformational disease. Work in our laboratory aims to elucidate the mechanisms by which proteins fold or misfold and aggregate, so as to provide information key to the development of therapeutics against misfolding disease. In the lecture I will discuss the nature of protein folding and misfolding landscapes and discuss recent data from our laboratory that have focused on developing an armoury of biochemical and biophysical methods to elucidate the mechanism of amyloid formation at a structural molecular level. In particular, focusing on the protein, beta-2-microglobulin, I will discuss exciting new insights into the structural molecular mechanism of amyloid assembly and describe recent data from our laboratory which suggest that amyloid fibrils may be more than just the inert end products of protein fibrillation.

8 Feb 2011

Jim Naismith

St Andrews

Conformational states of membrane proteins

Abstract

Membrane proteins are often claimed (possibly over hyped) as the last great frontier of structural biology. It is certainly true that obtaining high quality structural data is challenging. In common with other conventional structural biology, a structure is not enough. One of the issues facing the study of membrane protein is the need to shed light upon the function and this involves mapping out different conformational states. Relying solely on protein crystallography is problematic but modelling alone may have issues. I will discuss a system where protein crystallography has been used to identify motion but highlight the issues with this approach and contrast it with modelling approaches. I will present some new data using EPR which may leverage crystallographic data and provide better restraints upon modelling.

20 Jan 2011

Christian Speck, PhD

DNA Replication Group, MRC Clinical Sciences Centre, Hammersmith Hospital

Initiating Eukaryotic Replication: Loading of a Helicase at a DNA Replication Origin

13 Jan 2011

Prof Francis Barr

University of Liverpool
CR-UK Cancer Research Centre

New insights into the regulation and function of Polo and Aurora kinases in mitosis and cytokinesis

Abstract

Dynamic protein phosphorylation, mediated by a conserved cohort of protein kinases controls the profound changes in cellular organization required for mitosis and cytokinesis. Many of these kinases share a common activation mechanism involving phosphorylation of a threonine residue within the activation or T-loop, and binding to a co-activator protein. In this seminar I will discuss recent work on Polo-like kinase 1 and Aurora A, highlighting the importance of specific T-loop phosphatases for spatial control of kinase activation and progress in the identification of key substrates for these kinases.