Professor Jon Waltho
School of Biosciences
Gibson Chair in Biophysics
+44 114 222 2717
Full contact details
School of Biosciences
Firth Court
Western Bank
91直播
S10 2TN
- Profile
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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 91直播
- 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
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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鈥檚, 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 , 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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Show: Featured publications All publications
Featured publications
Journal articles
All publications
Journal articles
- . Structure, S0969-2126(24)00270.
- . Journal of Molecular Biology, 435(15), 168158-168158.
- . ACS Catalysis, 2021(11), 12840-12849.
- . Magnetic Resonance, 2(2), 629-642.
- . Green Chemistry, 23(2), 752-762.
- . Communications Biology, 3(1).
- . Nature Communications, 11(1).
- . Communications Chemistry, 3(1).
- . Structure.
- . Journal of Cell Science.
- . ACS Catalysis, 9(5), 4394-4401.
- . Biomolecular NMR Assignments, 13(2), 349-356.
- . ACS Catalysis, 8(12), 11589-11599.
- . ACS Catalysis, 8(9), 8140-8153.
- . Nucleic Acids Research, 46(11), 5618-5633.
- . Journal of Biological Chemistry, 293(24), 9301-9310.
- . Biomolecular NMR Assignments, 12(1), 79-83.
- . Biomolecular NMR Assignments, 11(2), 251-256.
- . Angewandte Chemie, 129(33), 9864-9867.
- . Angewandte Chemie International Edition, 56(33), 9732-9735.
- . Pure and Applied Chemistry, 89(5), 653-675.
- . Angewandte Chemie, 129(15), 4172-4192.
- . Angewandte Chemie International Edition, 56(15), 4110-4128.
- . Biomolecular NMR Assignments.
- . Angewandte Chemie, 128(10), 3379-3383.
- . Angewandte Chemie International Edition, 55(10), 3318-3322.
- . Journal of Biological Chemistry, 290(48), 28708-28723.
- . Journal of Molecular Biology, 427(15), 2418-2434.
- . Journal of Biomolecular NMR, 62(1), 43-52.
- . Journal of Biological Chemistry, 289(37), 25497-25508.
- . Proceedings of the National Academy of Sciences, 111(34), 12384-12389.
- . Alzheimer's & Dementia, 10, P494-P494.
- . Journal of Molecular Biology.
- . Angewandte Chemie, 125(44), 11830-11833.
- . Angew Chem Int Ed Engl, 52(44), 11616-11619.
- . Alzheimer's & Dementia, 9, P361-P362.
- . J Am Chem Soc, 135(7), 2512-2517.
- . Angewandte Chemie, 124(49), 12408-12411.
- . Proc Natl Acad Sci U S A, 109(48), 19563-19568.
- . Angew Chem Int Ed Engl, 51(49), 12242-12245.
- . Frontiers in Molecular Neuroscience(AUG 2012), 1-30.
- . BIOCHEMISTRY-MOSCOW, 77(10), 1083-1096.
- . Journal of Biological Chemistry, 287(17), 14023-14039.
- . Proc Natl Acad Sci U S A, 109(18), 6910-6915.
- Non-toxic Salvia sclareoides Brot. extracts as a source of functional food ingredients: Phenolic profile, antioxidant activity and prion binding properties. Food Chemistry.
- . Food Chemistry, 132(4), 1930-1935.
- . Chemistry, 17(35), 9753-9761.
- . Biophys J, 100(9), 2268-2274.
- . J Am Chem Soc, 133(11), 3989-3994.
- . Proc Natl Acad Sci U S A, 107(41), 17610-17615.
- . Biochemistry, 49(40), 8729-8738.
- A Pharmacological Chaperone for the Structured Domain of Human Prion Protein. PRION, 4(3), 130-130.
- . J Am Chem Soc, 132(18), 6507-6516.
- . Proc Natl Acad Sci U S A, 107(10), 4555-4560.
- . J Mol Biol, 396(2), 345-360.
- . NEW J CHEM, 34(5), 784-794.
- . J Am Chem Soc, 131(45), 16334-16335.
- . J Biol Chem, 284(33), 21981-21990.
- . J Biol Chem, 284(27), 18160-18166.
- . Proc Natl Acad Sci U S A, 106(14), 5651-5656.
- . J Am Chem Soc, 131(4), 1575-1588.
- . Proteins, 74(2), 425-436.
- . J Mol Biol, 385(1), 266-277.
- . Biochemistry, 47(51), 13620-13634.
- . Free Radic Biol Med, 45(9), 1271-1278.
- . J Am Chem Soc, 130(12), 3952-3958.
- . J Mol Biol, 375(2), 487-498.
- . J Mol Biol, 366(5), 1569-1579.
- . Biochem J, 400(3), 501-510.
- . J Mol Biol, 364(4), 810-823.
- . Biochem J, 399(3), 435-444.
- . Proc Natl Acad Sci U S A, 103(40), 14732-14737.
- . J Mol Biol, 358(5), 1353-1366.
- . J Mol Biol, 357(2), 365-372.
- . Proteins, 62(4), 918-927.
- . J Virol, 80(3), 1451-1462.
- . Chemistry, 12(4), 1081-1087.
- . Biochemistry, 44(50), 16649-16657.
- . Structure, 13(7), 963-971.
- . Structure, 13(4), 609-616.
- . Mol Biol Cell, 16(4), 2049-2057.
- . Chem Biol, 12(1), 89-97.
- . J Biol Chem, 279(27), 28515-28521.
- . Chemistry, 10(7), 1705-1710.
- . Proteins, 54(3), 500-512.
- . J Mol Biol, 336(2), 497-508.
- . J Mol Biol, 336(1), 165-178.
- . J Mol Biol, 330(5), 1189-1201.
- . J Biol Chem, 278(17), 15304-15312.
- . Biophys J, 83(2), 1177-1183.
- . Biochem Soc Trans, 30(4), 543-547.
- Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily.. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 223, C36-C36.
- . EMBO J, 20(17), 4774-4781.
- . Nat Struct Biol, 8(8), 701-704.
- . Proc Natl Acad Sci U S A, 98(15), 8531-8535.
- A rational approach to identifying treatments for prion diseases. FUNDAMENTAL & CLINICAL PHARMACOLOGY, 15, 112-112.
- . Biochemistry, 39(51), 15783-15790.
- . J Org Chem, 65(24), 8406.
- . Proc Natl Acad Sci U S A, 97(11), 5790-5795.
- . Neurobiology of Aging, 21, 209-209.
- Erratum: Computer-assisted structure determination. Structure of the peptide moroidin from Laportea moroides (Journal of Organic Chemistry (1989) 54 (1901)). Journal of Organic Chemistry, 65(24), 8406-8406.
- Letter to the Editor: Backbone NMR assignment of the 19 kDa translationally controlled tumor-associated protein p23(fyp) from Schizosaccharomyces pombe. J BIOMOL NMR, 16(1), 83-84.
- . J Biomol NMR, 16(1), 83-84.
- . Nat Struct Biol, 6(8), 740-743.
- Differences in the effects of TFE on the folding pathways of human stefins A and B.. Proteins, 36(2), 205-216.
- . J Biol Chem, 274(23), 16077-16084.
- . Biochim Biophys Acta, 1431(1), 1-13.
- . Science, 283(5409), 1935-1937.
- . J Mol Biol, 286(2), 389-401.
- . J Mol Biol, 284(5), 1625-1639.
- On the mechanism of human stefin B folding: I. Comparison to homologous stefin A. Influence of pH and trifluoroethanol on the fast and slow folding phases.. Proteins, 32(3), 296-303.
- . Proteins, 32(3), 304-313.
- . Biochemistry, 37(20), 7551-7560.
- . Nat Struct Biol, 5(3), 194-198.
- . Nat Struct Biol, 4(10), 801-804.
- . Curr Opin Biotechnol, 8(4), 400-410.
- Double and triple resonance NMR methods for protein assignment., 60, 29-52.
- . Biochemistry, 36(2), 333-340.
- . Methods Mol Biol, 60, 29-52.
- . Biochemistry, 35(49), 15740-15752.
- . Biochemistry, 35(32), 10287-10299.
- . Mol Cell Biol, 16(7), 3338-3349.
- . Nat Struct Biol, 2(9), 777-783.
- ASYMMETRY IN THE STRUCTURE OF GLYCOPEPTIDE ANTIBIOTIC DIMERS - NMR-STUDIES OF THE RISTOCETIN-A COMPLEX WITH A BACTERIAL-CELL WALL ANALOG. J AM CHEM SOC, 117(30), 7958-7964.
- THE BINDING OF A HYDROPHOBIC DRUG TO THE C-TERMINAL DOMAIN OF CALMODULIN. J CELL BIOCHEM, 70-70.
- THE REFINED SOLUTION STRUCTURE OF HUMAN STEFIN-A. J CELL BIOCHEM, 40-40.
- . J Biol Chem, 270(11), 5805-5811.
- . J Mol Biol, 246(2), 331-343.
- THE ACTION OF TIME-DOMAIN CONVOLUTION FILTERS FOR SOLVENT SUPPRESSION. J MAGN RESON SER B, 106(1), 40-46.
- . FEBS Lett, 355(1), 57-60.
- MOLECULAR ZIPPERS. J AM CHEM SOC, 116(22), 10292-10293.
- . Eur J Biochem, 225(3), 1181-1194.
- . Biochem J, 298 Pt 3, 727-732.
- FOLDING PATHWAY OF APOMYOGLOBIN. ABSTR PAP AM CHEM S, 206, 107-PHYS.
- PRACTICAL ASPECTS OF RECORDING MULTIDIMENSIONAL NMR-SPECTRA IN WATER WITH FLAT BASE-LINES. J MAGN RESON SER A, 103(3), 338-348.
- . Biochemistry, 32(25), 6337-6347.
- . Biochemistry, 32(25), 6348-6355.
- . Biochemistry, 32(25), 6356-6364.
- STRUCTURE DETERMINATION OF HUMAN ELAFIN. J CELL BIOCHEM, 286-286.
- PEPTIDE STRUCTURE FROM NMR. CHEM SOC REV, 21(4), 227-236.
- IMPROVED EXPERIMENTS FOR THE ASSIGNMENT OF CROWDED PEPTIDE SPECTRA. J MAGN RESON, 100(3), 593-597.
- . J Mol Biol, 226(3), 795-817.
- . Biochem Soc Trans, 19(4), 430S.
- THE NATURAL DESIGN OF VANCOMYCIN FAMILY ANTIBIOTICS TO BIND THEIR TARGET PEPTIDES. CIBA F SYMP, 158, 73-91.
- . Ciba Found Symp, 158, 73-86.
- . ChemInform, 20(28).
- . FEBS Lett, 250(2), 400-404.
- COMPUTER-ASSISTED STRUCTURE DETERMINATION - STRUCTURE OF THE PEPTIDE MOROIDIN FROM LAPORTEA-MOROIDES. J ORG CHEM, 54(8), 1901-1904.
- ASPECTS OF MOLECULAR RECOGNITION - SOLVENT EXCLUSION AND DIMERIZATION OF THE ANTIBIOTIC RISTOCETIN WHEN BOUND TO A MODEL BACTERIAL CELL-WALL PRECURSOR. J AM CHEM SOC, 111(7), 2475-2480.
- MOLECULAR-BASIS OF THE ACTIVITY OF ANTIBIOTICS OF THE VANCOMYCIN GROUP. PURE APPL CHEM, 61(3), 585-588.
- . ChemInform, 19(49).
- INTRAMOLECULAR DETERMINANTS OF CONFORMATION AND MOBILITY WITHIN THE ANTIBIOTIC VANCOMYCIN. J AM CHEM SOC, 110(17), 5638-5643.
- . ChemInform, 19(33).
- ASPECTS OF MOLECULAR RECOGNITION - USE OF A TRUNCATED DRIVEN PSEUDO-NOESY EXPERIMENT TO ELUCIDATE THE ENVIRONMENT OF INTERMOLECULAR ELECTROSTATIC INTERACTIONS IN VANCOMYCIN. J CHEM SOC CHEM COMM(11), 707-709.
- FUNCTION OF THE AMINO SUGAR AND N-TERMINAL AMINO-ACID OF THE ANTIBIOTIC VANCOMYCIN IN ITS COMPLEXATION WITH CELL-WALL PEPTIDES. J AM CHEM SOC, 110(9), 2946-2953.
- . J Comput Aided Mol Des, 2(1), 31-41.
- . Biochem Pharmacol, 37(1), 133-141.
- . ChemInform, 18(52).
- STRUCTURE ELUCIDATION OF THE GLYCOPEPTIDE ANTIBIOTIC COMPLEX A40926. J CHEM SOC PERK T 1(9), 2103-2107.
- SEMISELECTIVE TWO-DIMENSIONAL NMR EXPERIMENTS. J MAGN RESON, 74(2), 386-393.
- . Chemischer Informationsdienst, 17(51).
- STRUCTURE ELUCIDATION OF 2 TRITERPENOID TETRASACCHARIDES FROM ANDROSACE-SAXIFRAGIFOLIA. J CHEM SOC PERK T 1(8), 1527-1531.
- Peri active site catalysis of proline isomerisation is the molecular basis of allomorphy in 尾-phosphoglucomutase. Communications Biology.
- . ACS Catalysis, 6650-6658.
- . Biomolecular NMR Assignments.
- An enzyme with high catalytic proficiency utilizes distal site substrate binding energy to stabilize the closed state but at the expense of substrate inhibition. ACS Catalysis.
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- . Physical Chemistry Chemical Physics, 17(2), 762-782.
- . ChemInform, 41(34), no-no.
- . ChemInform, 24(12), no-no.
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Chapters
- , Methods in Enzymology (pp. 145-166). Elsevier
- Architecture of the active site and the importance of charge balance in catalysis, Phosphoglycerate Kinase: A Hinge-Bending Enzyme (pp. 203-210).
- , Current Research in Protein Chemistry (pp. 283-293). Elsevier
Conference proceedings papers
- Substrate discrimination via a proline switch in an allomorphic enzyme. PROTEIN SCIENCE, Vol. 30 (pp 101-101)
- The Catalytic Cycle of hFEN1 Requires Protein and DNA Conformational Changes, but Are They Rate-Limiting?. PROTEIN SCIENCE, Vol. 24 (pp 147-147)
- 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
- Kinases, phosphatases, mutases and G-proteins. FEBS JOURNAL, Vol. 280 (pp 93-93)
- Computational studies of intermediate- and transition-state analogs in b-PGM. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, Vol. 245
- 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
- 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)
- . Biophysical Journal, Vol. 96(3) (pp 322a-323a)
- A model for amyloid fibril formation by human stefin B (cystatin B). FEBS JOURNAL, Vol. 275 (pp 199-199)
- FOLDING OF PEPTIDE-FRAGMENTS OF PROTEINS IN WATER SOLUTION. PROTEIN FOLDING : DECIPHERING THE SECOND HALF OF THE GENETIC CODE (pp 95-+)
- FOLDING OF PEPTIDE-FRAGMENTS OF PROTEINS IN AQUEOUS-SOLUTION. FRONTIERS OF NMR IN MOLECULAR BIOLOGY, Vol. 109 (pp 1-13)
Preprints
- Teaching activities
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Level 3 modules
- MBB302 Physical Methods for Studying Biological Structures
- MBB310 Assembly of Supramolecular Structures