Protein Crystallography and Bioinformatics

Prof P J Artymiuk

My laboratory works on both experimental and theoretical aspects of protein structure analysis:

X-ray crystallography is used experimentally to determine macromolecular structures and to study the relationship between structure and function in proteins of biological and medical interest. Projects underway include: the DNA-binding regulator of fumarate and nitrate reduction from Lactobacillus casei; flap endonuclease enzymes, and members of a novel hemolysin family of proteins from E. coli and Bacillus cereus. The structure of the E. coli toxin hemolysin E has revealed the molecular architecture of a new family of toxins and suggests a novel mode of membrane interaction.

Figure legend. Model of hemolysin E forming membrane pore.

Therapeutic biomolecules with enhanced characteristics. Protein molecules are now used therapeutically in medicine but many of these molecules are cleared from the circulation by the kidneys or by proteolysis within hours or minutes of administration. In collaboration with scientists in the Medical School, our start-up company Asterion Ltd has been developing methods to extend the lifetimes of therapeutic biomolecules such as human growth hormone, erythropoietin and GCSF in the circulation.

Bioinformatics and theoretical techniques. There is a vast amount of information now available on biological macromolecules. This information can only be exploited to its full potential if methods are developed to help detect and clarify the complex relationships between these molecules. In collaboration with information and computer scientists, we are developing algorithms to: (a) compare the 3-dimensional folds of protein structures; (b) identify patterns of sidechains; (c) investigate the rapidly expanding database of complex RNA 3-dimensional structures; and (d) devise new methods for representing protein surfaces. The use of genetic algorithms is also showing promise in a variety of structural problems ranging from determination of heavy atom positions in crystallography to comparison of protein surfaces.

protein homology

Figure Legend - Structural similarity between the catalytic domain of adenylyl cyclase (AC, right) and the palm domain of DNA polymerase I (left), which has revealed the likely location of the active site of AC.

Selected Publications

Assessing the role of Asp 194 in the transmembrane domains of the α-chain of the high-affinity receptor complex for Immunoglobulin E in signal transduction. A. Rashid, M.W. Iodice, K.M. Carroll, J.E.M. Housden, P.J. Artymiuk, B.A. Helm. Molecular Immunology 48: 128-136 (2010)

Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand-receptor fusions. E Ferrandis, S.L. Pradhananga, C. Touvay, C. Kinoshita, I.R. Wilkinson, K. Stafford, Z. Wu, C.J. Strasburger, J.R. Sayers, P.J. Artymiuk, and R. J. Ross. Clinical Science 119: 483-491 (2010)

Mycobacterium tuberculosis cAMP receptor protein (Rv3676) differs from the Escherichia coli paradigm in its cAMP-binding, DNA-binding and transcription activation properties. Stapleton M, Haq I, Hunt DM, Arnvig KB, Artymiuk PJ, Buxton RS, Green J. J Biol Chem.285:7016-7027(2009)

The O₂ sensitivity of the transcription factor FNR is controlled by Ser24 modulating the kinetics of [4Fe-4S] to [2Fe-2S] conversion. Jervis AJ, Crack JC, White G, Artymiuk PJ, Cheesman MR, Thomson AJ, Le Brun NE, Green J. Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4659-64.

The formation and structure of Escherichia coli K-12 haemolysin E pores. Hunt S, Moir AJ, Tzokov S, Bullough PA, Artymiuk PJ, Green J. Microbiology. 2008 Feb;154(Pt 2):633-42

A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist. Wilkinson IR, Ferrandis E, Artymiuk PJ, Teillot M, Soulard C, Touvay C, Pradhananga SL, Justice S, Wu Z, Leung KC, Strasburger CJ, Sayers JR, Ross RJ. Nature Medicine 2007 Sep;13(9):1108-13.

Structure of the hemolysin E (HlyE, ClyA, and SheA) channel in its membrane-bound form. Tzokov SB, Wyborn NR, Stillman TJ, Jamieson S, Czudnochowski N, Artymiuk PJ, Green J, Bullough PA. J Biol Chem. 2006 Aug 11;281(32):23042-9.

The double life of aconitase. Artymiuk PJ, Green J. Structure. 2006 Jan;14(1):2-4.

E.coli hemolysin E (HlyE, ClyA, SheA): X-ray crystal structure of the toxin and observation of membrane pores by electron microscopy. A.J.Wallace, T.J.Stillman, A.Atkins, S.J.Jamieson, P.A.Bullough, J.Green, & P.J.Artymiuk. Cell 100: 265-276 (2000)

Crystal structure of manganese catalase from Lactobacillus plantarum V.V.Barynin, M.M.Whittaker, S.V.Antonyuk, V.S.Lamzin, P.M.Harrison, P.J.Artymiuk & J.W.Whittaker. Structure 9: 725-738 (2001)

E. coli aconitase B structure reveals a HEAT-like domain with implications for protein-protein recognition. C.H.Williams, T.J.Stillman, V.V.Barynin, S.E.Sedelnikova, Y.Tang, J.Green, J.R.Guest & P.J.Artymiuk. Nature Struct. Biol. 9: 447-452 (2002)

Interactions of mutant and wild-type flap endonucleases with oligonucleotide substrates suggest an alternative model of DNA binding. J.J.Dervan, M.Feng, D.Patel, J.A.Grasby, P.J.Artymiuk, C.A.Ceska and J.R.Sayers. Proc. Natl. Acad. Sci. U.S.A. 99: 8542-8547 (2002)

Protein Structures and Information Extraction from Biological Texts: The PASTA System. G.Demetriou, R.Gaizauskas, P.Artymiuk and P.Willett. Bioinformatics 19: 135-143 (2003)

GAPDOCK: A genetic algorithm approach to protein docking in Capri round 1. E.J.Gardiner, P.Willett and P.J.Artymiuk Proteins 53: 10-14 (2003)