Professor Jon Waltho

School of Biosciences

Gibson Chair in Biophysics

Jon Waltho
Profile picture of Jon Waltho
j.waltho@sheffield.ac.uk
+44 114 222 2717

Full contact details

Professor Jon Waltho
School of Biosciences
Firth Court
Western Bank
Sheffield
S10 2TN
Profile

Research focuses on the use of high field NMR spectroscopy to determine the structure and function of proteins and how they fold from their fully unfolded states.

Career history

  • 2009: Awarded the Gibson Chair of Biophysics
  • 2008: Professorial Appointment in Faculty of Life Sciences, University of Manchester
  • 1999: Awarded a Personal Chair in Molecular Biology and Biotechnology
  • 1997: Promoted to a Readership
  • 1996: Awarded a Research Fellowship by the Lister Institute of Preventive Medicine
  • 1996: Promoted to a Senior Lectureship
  • 1990: Awarded a Krebs Institute Lectureship in the Department of Molecular Biology and Biotechnology, University of Sheffield
  • 1987 - 90: Postdoctoral research assistant, with Dr P. E. Wright, Department of Molecular Biology, The Scripps Research Institute, La Jolla, California
  • 1986 - 87: Postdoctoral research assistant, with Dr J. G. Vinter, SmithKline French Research
  • 1983 - 86: Postgraduate studentship, SERC funded, with Dr D. H. Williams in the University Chemical Laboratory and Emmanual College, Cambridge
Research interests

Our laboratory focuses on the use of high field NMR spectroscopy to determine the structure and function of proteins and how they fold from their fully unfolded states. Our studies address both fundamental aspects of protein biophysics and dynamics, and the investigation of the biomedical targets and their inhibition.

Recent highlights include the structure determination and characterisation of the solution dynamics of the human intracellular cysteine proteinase inhibitor stefin A. Proteins of this family inhibit enzymes central to the invasion of the body by foreign organisms (e.g. trypanosomes that cause African Sleeping sickness) and the entry of metastatic cancer cells into new tissues.

In addition, the absence of the protein stefin B was recently the first identified genetic cause of epilepsy.

Structure and dynamic measurements of stefins provide insights into means of developing small molecule pharmaceuticals that mimic the protective function of this class of proteins.

Understanding how proteins fold is both a major goal from a viewpoint of fundamental biochemistry, and is of growing biomedical importance owing its implication in a variety of neurodegenerative diseases.

Diseases ranging from Alzheimer’s, through amyloid angiopathy to the prion diseases, CJD and BSE, appear to utilise partially and misfolded states of proteins.

We have shown how NMR can be used to determine structural and dynamic information of such states, which provide a basis for identifying where and how to interrupt amyloidogenesis before the onset of neurodegeneration. We focus on three proteins in this regard, cystatin C, human prion protein and phosphoglycerate kinase (PGK).

Enzymes that catalyse phosphoryl transfer include kinases, ATPases and phosphatases, and therefore constitute arguably the most important group of enzymes. They increase the reaction rate by up to 1020-fold - a truly remarkable rate increase.

Studies by our group, reported in Angewandte Chemie 2017 56:4110, use a combination of X-ray crystallography, NMR, and computational analysis, using metal fluorides as analogues of the phosphate group.

They show how these enzymes use a combination of precise geometrical positioning, charge balance, and control of hydrogen bonds, to achieve their rate enhancements. They also show how much we still have to learn.

Publications

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Journal articles

All publications

Journal articles

Chapters

Conference proceedings papers

  • Navarrete FAC, Baxter NJ, Buzoianu A, Wood HP, Hounslow AM & Waltho JP (2021) Substrate discrimination via a proline switch in an allomorphic enzyme. PROTEIN SCIENCE, Vol. 30 (pp 101-101) RIS download Bibtex download
  • Finger LD, Bennet IA, Hounslow A, Exell JC, Baxter NJ, Waltho JP & Grasby JA (2015) The Catalytic Cycle of hFEN1 Requires Protein and DNA Conformational Changes, but Are They Rate-Limiting?. PROTEIN SCIENCE, Vol. 24 (pp 147-147) RIS download Bibtex download
  • Molt R, Jin Y, Pellegrini E, Bowler M, Richards N, Blackburn GM & Waltho J (2015) Extended series of proximal and distal hydrogen bonds underpins RhoA catalyzed GTP hydrolysis via a strain-free transition state. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, Vol. 250 RIS download Bibtex download
  • Waltho J (2013) Kinases, phosphatases, mutases and G-proteins. FEBS JOURNAL, Vol. 280 (pp 93-93) RIS download Bibtex download
  • Leigh KN, Waltho JP, Blackburn GM, Bowler MW & Webster CE (2013) Computational studies of intermediate- and transition-state analogs in b-PGM. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, Vol. 245 RIS download Bibtex download
  • Leigh KN, Waltho JP, Blackburn GM, Bowler MW & Webster CE (2012) Utilization of computed F-19 NMR to identify active site intermediate and transition-state analogs in beta-PGM. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, Vol. 244 RIS download Bibtex download
  • Briggs DC, Ali T, Tongsoongnoen W, Rugg MS, Waltho JP, Levoli E, Mikecz K, Salustri A, Milner CS & Day AJ (2010) Towards the molecular basis of cumulus matrix formation: structure/function studies on TSG-6. INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Vol. 91(6) (pp A31-A31) RIS download Bibtex download
  • Volk M, Milanesi L, Waltho JP, Hunter CA, Dev S, Shaw DJ, Beddard GS & Reid GD (2009) Universal Scaling Law for Polypeptide Backbone Dynamics on the Pico- to Millisecond Time Scale. Biophysical Journal, Vol. 96(3) (pp 322a-323a) RIS download Bibtex download
  • Skerget K, Vilfan A, Waltho JP, Turk D & Zerovnik E (2008) A model for amyloid fibril formation by human stefin B (cystatin B). FEBS JOURNAL, Vol. 275 (pp 199-199) RIS download Bibtex download
  • WRIGHT PE, DYSON HJ, WALTHO JP & LERNER RA (1990) FOLDING OF PEPTIDE-FRAGMENTS OF PROTEINS IN WATER SOLUTION. PROTEIN FOLDING : DECIPHERING THE SECOND HALF OF THE GENETIC CODE (pp 95-+) RIS download Bibtex download
  • WRIGHT PE, DYSON HJ, FEHER VA, TENNANT LL, WALTHO JP, LERNER RA & CASE DA (1990) FOLDING OF PEPTIDE-FRAGMENTS OF PROTEINS IN AQUEOUS-SOLUTION. FRONTIERS OF NMR IN MOLECULAR BIOLOGY, Vol. 109 (pp 1-13) RIS download Bibtex download

Preprints

Teaching activities

Level 3 modules

  • MBB302 Physical Methods for Studying Biological Structures
  • MBB310 Assembly of Supramolecular Structures