Professor David Middleton

Professor

Research Overview

In my research I use solid-state NMR to examine molecular structure, function and dynamics. Current research falls broadly into two areas:

1. Solid-state NMR methods to determine the structure and interactions of pharmaceutical molecules in their site of action in biological receptor targets. Current targets of interest are membrane embedded proteins, including the digitalis receptor and its interaction with cardiac glycosides, amyloid polypeptides and their interactions with carbohydrates and cardiac calcium handling proteins as targets for heart failure.

2. Magic-angle spinning and oriented sample NMR methods to probe the molecular architectures of novel, biologically-inspired nanomaterials, including peptide nanotubes and peptide-capped nanoparticles for biocompatible applications.

Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids
Tang, H., Ruan, L., Tian, H., Liang, G., Ye, W., Hughes, E., Esmann, M., Fedosova, N.U., Chung, T., Tzen, J.T.C., Jiang, R., Middleton, D.A. 5/07/2016 In: Scientific Reports. 2016, 6, 10 p.
Journal article

Long-range effects of Na+ binding in Na,K-ATPase reported by ATP
Middleton, D.A., Fedosova, N.U., Esmann, M. 1/12/2015 In: Biochemistry. 54, 47, p. 7041-7047. 7 p.
Journal article

Comparisons with amyloid-β reveal an aspartate residue that stabilizes fibrils of the aortic amyloid peptide medin
Davies, H., Madine, J., Middleton, D. 20/03/2015 In: Journal of Biological Chemistry. 290, p. 7791-7803. 13 p.
Journal article

Ligand orientation in a membrane-embedded receptor site revealed by solid-state NMR with paramagnetic relaxation enhancement.
Whittaker, C., Patching, S., Esmann, M., Middleton, D. 7/03/2015 In: Organic and Biomolecular Chemistry . 13, 9, p. 2664-2668. 5 p.
Journal article

Structures, chemotaxonomic significance, cytotoxic and Na+, K+-ATPase inhibitory activities of new cardenolides from Asclepias curassavica
Zhang, R., Tian, H., Tan, Y., Chung, T., Sun, X., Xia, X., Ye, W., Middleton, D.A., Fedosova, N., Esmann, M., Tzen, J.T.C., Jiang, R. 17/09/2014 In: Organic and Biomolecular Chemistry . 12, 44, p. 8919-8929. 11 p.
Journal article

Comparison of the structure and function of phospholamban and the Arginine-14 deficient mutant associated with dilated cardiomyopathy
Hughes, E., Middleton, D.A. 16/09/2014 In: PLoS ONE. 9, 9, 10 p.
Journal article

Synthesis of bufalin derivatives with inhibitory activity against prostate cancer cells
Yuan, X., Tian, H., Li, J., Jin, L., Jiang, S., Liu, K.W., Luo, C., Middleton, D.A., Esmann, M., Ye, W., Jiang, R. 3/06/2014 In: Natural Product Research. 28, 11, p. 843-847. 5 p.
Journal article

Expression and purification of the aortic amyloid polypeptide medin
Davies, H.A., Wilkinson, M.C., Gibson, R.P., Middleton, D.A. 06/2014 In: Protein Expression and Purification. 98, p. 32-37. 6 p.
Journal article

Heparin promotes the rapid fibrillization of a peptide with low intrinsic amyloidogenicity
Madine, J., Davies, H.A., Hughes, E., Middleton, D.A. 17/12/2013 In: Biochemistry. 52, 50, p. 8984-8992. 9 p.
Journal article

Insights into the Molecular Architecture of a Peptide Nanotube Using FTIR and Solid-State NMR Spectroscopic Measurements on an Aligned Sample
Middleton, D.A., Madine, J., Castelletto, V., Hamley, I.W. 27/09/2013 In: Angewandte Chemie International Edition. 52, 40, p. 10537-10540.
Journal article

Probing the contacts of a low-affinity substrate with a membrane-embedded transport protein using 1H-13C cross-polarisation magic-angle spinning solid-state NMR
Patching, S.G., Henderson, P.J.F., Sharples, D.J., Middleton, D.A. 03/2013 In: Molecular Membrane Biology. 30, 2, p. 129-37. 9 p.
Journal article

Site-specific identification of an aβ fibril-heparin interaction site by using solid-state NMR spectroscopy
Madine, J., Pandya, M.J., Hicks, M.R., Rodger, A., Yates, E.A., Radford, S.E., Middleton, D.A. 21/12/2012 In: Angewandte Chemie International Edition. 51, 52, p. 13140-3. 4 p.
Journal article

Fibrils and nanotubes assembled from a modified amyloid-β peptide fragment differ in the packing of the same β-sheet building blocks
Madine, J., Davies, H.A., Shaw, C., Hamley, I.W., Middleton, D.A. 21/03/2012 In: Chemical Communications. 48, 24, p. 2976-8. 3 p.
Journal article

Amyloid-derived peptide forms self-assembled monolayers on gold nanoparticle with a curvature-dependent β-sheet structure
Shaw, C.P., Middleton, D.A., Volk, M., Lévy, R. 28/02/2012 In: ACS Nano. 6, 2, p. 1416-26. 11 p.
Journal article

Solid-state NMR reveals differences in the packing arrangements of peptide aggregates derived from the aortic amyloid polypeptide medin
Davies, H.A., Madine, J., Middleton, D.A. 01/2012 In: Journal of Family Psychology. 18, 1, p. 65-72. 8 p.
Journal article

The conformation of ATP within the Na,K-ATPase nucleotide site: a statistically constrained analysis of REDOR solid-state NMR data
Middleton, D.A., Hughes, E., Esmann, M. 25/07/2011 In: Angewandte Chemie International Edition. 50, 31, p. 7041-4. 4 p.
Journal article

A study of the membrane association and regulatory effect of the phospholemman cytoplasmic domain
Hughes, E., Whittaker, C.A.P., Barsukov, I.L., Esmann, M., Middleton, D.A. 04/2011 In: Biochimica et Biophysica Acta (BBA) - Biomembranes. 1808, 4, p. 1021-31. 11 p.
Journal article

Solid-state NMR detection of 14N-13C dipolar couplings between amino acid side groups provides constraints on amyloid fibril architecture
Middleton, D.A. 02/2011 In: Journal of Family Psychology. 49, 2, p. 65-9. 5 p.
Journal article

Measurement of multiple torsional angles from one-dimensional solid-state NMR spectra: application to the conformational analysis of a ligand in its biological receptor site
Edwards, R., Madine, J., Fielding, L., Middleton, D.A. 14/11/2010 In: Journal of Family Psychology. 12, 42, p. 13999-4008. 10 p.
Journal article

Heparin-derived oligosaccharides interact with the phospholamban cytoplasmic domain and stimulate SERCA function
Hughes, E., Edwards, R., Middleton, D.A. 22/10/2010 In: Biochemical and Biophysical Research Communications. 401, 3, p. 370-5. 6 p.
Journal article

Comparison of aggregation enhancement and inhibition as strategies for reducing the cytotoxicity of the aortic amyloid polypeptide medin
Madine, J., Middleton, D.A. 08/2010 In: Journal of Family Psychology. 39, 9, p. 1281-8. 8 p.
Journal article

Evaluation of beta-alanine- and GABA-substituted peptides as inhibitors of disease-linked protein aggregation
Madine, J., Wang, X., Brown, D.R., Middleton, D.A. 17/08/2009 In: Journal of Family Psychology. 10, 12, p. 1982-7. 6 p.
Journal article

Inhibitors of protein aggregation and toxicity
Amijee, H., Madine, J., Middleton, D.A., Doig, A.J. 08/2009 In: Biochemical Society Transactions. 37, Pt 4, p. 692-6. 5 p.
Journal article

Structural analysis of uniformly (13)C-labelled solids from selective angle measurements at rotational resonance
Patching, S.G., Edwards, R., Middleton, D.A. 08/2009 In: Journal of Family Psychology. 199, 2, p. 242-6. 5 p.
Journal article

Solid-state NMR studies of adenosine 5'-triphosphate freeze-trapped in the nucleotide site of Na,K-ATPase
Middleton, D.A., Hughes, E., Fedosova, N.U., Esmann, M. 20/07/2009 In: Journal of Family Psychology. 10, 11, p. 1789-92. 4 p.
Journal article

Exploiting a (13)C-labelled heparin analogue for in situ solid-state NMR investigations of peptide-glycan interactions within amyloid fibrils
Madine, J., Clayton, J.C., Yates, E.A., Middleton, D.A. 7/06/2009 In: Organic and Biomolecular Chemistry . 7, 11, p. 2414-20. 7 p.
Journal article

Cross-beta spine architecture of fibrils formed by the amyloidogenic segment NFGSVQFV of medin from solid-state NMR and X-ray fiber diffraction measurements
Madine, J., Copland, A., Serpell, L.C., Middleton, D.A. 14/04/2009 In: Biochemistry. 48, 14, p. 3089-99. 11 p.
Journal article

Cytoplasmic residues of phospholamban interact with membrane surfaces in the presence of SERCA: a new role for phospholipids in the regulation of cardiac calcium cycling?
Hughes, E., Clayton, J.C., Middleton, D.A. 02/2009 In: Biochimica et Biophysica Acta (BBA) - Biomembranes. 1788, 2, p. 559-66. 8 p.
Journal article

Structural insights into the polymorphism of amyloid-like fibrils formed by region 20-29 of amylin revealed by solid-state NMR and X-ray fiber diffraction
Madine, J., Jack, E., Stockley, P.G., Radford, S.E., Serpell, L.C., Middleton, D.A. 12/11/2008 In: Journal of the American Chemical Society. 130, 45, p. 14990-5001. 12 p.
Journal article

Relative substrate affinities of wild-type and mutant forms of the Escherichia coli sugar transporter GalP determined by solid-state NMR
Patching, S.G., Psakis, G., Baldwin, S.A., Baldwin, J., Henderson, P.J.F., Middleton, D.A. 09/2008 In: Molecular Membrane Biology. 25, 6-7, p. 474-84. 11 p.
Journal article

The effects of alpha-synuclein on phospholipid vesicle integrity: a study using 31P NMR and electron microscopy
Madine, J., Hughes, E., Doig, A.J., Middleton, D.A. 09/2008 In: Molecular Membrane Biology. 25, 6-7, p. 518-27. 10 p.
Journal article

Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR
Madine, J., Doig, A.J., Middleton, D.A. 25/06/2008 In: Journal of the American Chemical Society. 130, 25, p. 7873-81. 9 p.
Journal article

Solid-state NMR spectroscopy detects interactions between tryptophan residues of the E. coli sugar transporter GalP and the alpha-anomer of the D-glucose substrate
Patching, S.G., Henderson, P.J.F., Herbert, R.B., Middleton, D.A. 30/01/2008 In: Journal of the American Chemical Society. 130, 4, p. 1236-44. 9 p.
Journal article

The dynamics and orientation of a lipophilic drug within model membranes determined by 13C solid-state NMR
Boland, M.P., Middleton, D.A. 7/01/2008 In: Physical Chemistry Chemical Physics. 10, 1, p. 178-85. 8 p.
Journal article

Membrane interactions of peptides representing the polybasic regions of three Rho GTPases are sensitive to the distribution of arginine and lysine residues
Jack, E.R., Madine, J., Lian, L., Middleton, D.A. 01/2008 In: Molecular Membrane Biology. 25, 1, p. 14-22. 9 p.
Journal article