... understanding life in molecular detail

Dr Arnout Kalverda

NMR based Structural Biology, NMR method development, protein-ligand interactions, protein structure and dynamics 


NMR spectroscopy is a very powerful technique that can provide atomistic level information on biological systems directly in solution. We are studying protein structure and dynamics with a focus on viral proteins and viral-host protein interactions, partially folded proteins and protein-protein interactions in amyloid formation and the thermodynamics of protein-ligand interactions

Current major projects include:
  • Structural basis for viral antagonism of innate immunity
  • Partially folded and intrinsically disordered regions in proteins
  • Characterisation of conformationally exchanging systems
  • The role of dynamics in protein-ligand interactions

Structural basis for viral antagonism of innate immunity

The innate immune system recognizes pathogens through pattern recognition receptors such as Toll-like receptors (TLRs). Activation of these receptors initiates a complex signaling cascade leading to activation of NF-kB and interferon regulatory factors and release of pro-inflammatory cytokines. Aberrant activation of these pathways are associated with numerous inflammatory diseases. Many viruses express multiple proteins that antagonize the innate immune system. Learning about how these viral proteins interact with their host target proteins can reveal much about their functions in the innate immunity system and how viral proteins are able to interfere with these. We have solved the structure of the Vaccinia virus protein K7, a viral Bcl-2 homologue that inhibits activation of interferon regulatory factors IRF3 and IRF7. K7 interacts with a peptide motif in the intrinsically disordered N-terminal region of Dead Box RNA helicase 3 (DDX3). This clearly implicates the N-terminal region of DDX3 as being involved in the signaling cascade leading to activation of IRF3/7. Currently we are targeting the structure of A46, which is another representative of the group of Vaccinia virus proteins that antagonize the innate immune system.

Partially folded and intrinsically disordered regions in proteins

Many (especially eukaryotic) proteins contain intrinsically disordered regions of functional significance, while amyloid formation appears to occur under conditions that favour the population of partially folded conformations or unfolded state ensembles. NMR is uniquely positioned for obtaining structural information on such systems. NMR methods for the study of folded proteins or intrinsically disordered proteins are fairly well established, but systems with both folded and disordered regions remain challenging. We are looking into methods that allow the characterization of complex proteins that include both folded domains and disordered regions.

The role of dynamics in protein-ligand interactions

The binding affinity of a protein-ligand interaction is governed by its free energy difference which in turn has an enthalpic and entropic component. The entropy change is made up of contributions from the solvent, the ligand and the protein. Relaxation measurements are shedding light on the contribution of protein conformational dynamics to ligand binding and are showing that often entropy-entropy compensation mechanisms are at work in the protein's response. The reduction of rotational and translational entropy of the ligand is considered one of the most prominent entropic penalties in protein-ligand interactions. There is however very little direct experimental assessment of the amount of ligand motion either in the free state or the bound state. We are currently developing methods to measure the amount of residual motion of ligands in the bound state to gain a clearer insight in the ligand derived entropy changes in protein-ligand interactions.

Detailed research programme                  Close ▲
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NMR Facility Manager (Leeds) 1997-present
MSc (Wageningen) PhD (Leiden)


PhD (Leiden, The Netherlands) 1996
Postdoc (Leeds) 1995-1997

LC Miall 4.21a
School of Molecular and Cellular Biology
0113 3437997
A.Kalverda@leeds.ac.uk

Selected Publications

  1. Foster, T.L., Thompson, G.S., Kalverda, A.P., Kankanala, J., Bentham, M., Wetherill, L.F., Thompson, J., Barker, A.M., Clarke, D.,  Noerenberg, M., Pearson, A., Rowlands, D.J., Homans, S.W., Harris, M., Foster, R. & Griffin, S.D.C., Structure-guided design affirms inhibitors of Hepatitis C virus p7 as a viable class of antivirals targeting virion release. (2014) Hepatology 59:408-422.

  2. Eichner, T., Kalverda, A.P., Thompson, G.S., Homans, S.W. & Radford, S.E., Conformational conversion during amyloid formation at atomic resolution. (2011) Molecular Cell 41:161-172.

  3. Kalverda, A.P., Thompson, G.S., Vogel, A., Schröder, M., Bowie, A.G., Khan, A.R. & Homans, S.W., Poxvirus K7 protein adopts a Bcl-2 fold: Biochemical mapping of its interactions with human DEAD box RNA Helicase DDX3. (2009) Journal of Molecular Biology 385:843-853.

  4. Stöckmann, H., Bronowska, A., Syme, N.R., Thompson, G.S., Kalverda, A.P., Warriner, S.L. & Homans, S.W., Residual ligand entropy in the binding of p-substituted benzenesolfonamide ligands to bovine carbonic anhydrase II. (2008) Journal of the American Chemical Society 130:12420-12426.