Dr Adrian Lapthorn

Department of Chemistry
University of Glasgow
Glasgow G12 8QQ
Scotland

Telephone: +44 (0) 141 330 5940
FAX: +44 (0) 330 4888
email: adrian@chem.gla.ac.uk


My research interests are in using the technique of protein crystallography to elucidate protein structure with an aim to answering important questions on protein function and mechanism. I also have a specific interest in protein-protein interactions.

Glycoprotein hormones: This family of hormones has diverse functions and plays a fundamental role in reproductive endocrinology. The crystal structure of human chorionic gonadotropin (hCG) at 3.0Å, a hormone involved in the maintenance of the early stages of pregnancy, has given a wealth of information about this class of proteins. We now know that these hormones are comprised of similarly folded subunits containing cystine knots. The subunits are held together by a structurally unique feature, part of the peptide chain of the beta subunit wraps around the alpha subunit, locking it in place like a seat-belt. Thus these reproductive hormones are held together as if in a clasped embrace.

Structure of the hCG hetero dimer

References

A.M. Jackson, T Klonisch, A.J. Lapthorn, P. Berger, N.W. Isaacs, P.J. Delves, T. Lund and I. Roitt. (1996) Identification and selective destruction of shared epitopes in human chorionic gonadotropin beta subunit. J. Reprod. Immunol. 31, 21-36.

N. Bhowmick, J. Huang, D. Puett, N.W. Isaacs and A.J. Lapthorn. (1996) Determination of residues important in hormone binding to the extracellular domain of the Luteinizing Hormone/Chorionic Gonadotropin receptor by site directed mutagenesis and modelling. J. Mol. Endo. 10,1147-1159.


Enzymes of the shikimate pathway: The shikimate pathway is important for the synthesis of aromatic amino acids and related compounds. The pathway is present in bacteria, fungi and plants but importantly not in animals. The enzymes are the subject of intensive study at Glasgow in collaboration with Prof. J. Coggins, with the aim of developing novel antibiotics and herbicides by rational drug design. Enzymes presently under study are shikimate dehydrogenase, shikimate kinase and chorismate synthase. Chorismate synthase is of particular interest as it has been shown to be one of the sites of action of the Zeneca patented antibiotic fluoroshikimate. In addition, the reaction catalysed by chorismate synthase is an unusual anti 1,4-elimination, for which the mechanism is not known.

Crystals of shikimate kinase and the 3-D structure

References

T. Krell, J.E. Coyle, M.J. Horsburgh, J.R. Coggins, A.J. Lapthorn.(1997) Crystallisation and preliminary X-ray crystallographic analysis of shikimate kinase from Erwinia chrysanthemi. Acta. Cryst D53, 612-614.

C. Idziak, N.C. Price, S.M. Kelly, T. Krell, D.J. Boam, A.J.Lapthorn, J.R. Coggins.(1997) The interaction of shikimate kinase from Erwinia chrysanthemi with substrates. Biochem. Soc. Trans. 25, S627.

T. Krell, J.R. Coggins, A.J. Lapthorn.(1998) The three-dimensional structure of shikimate kinase from Erwinia chrysanthemi. J. Mol. Biol. 278, 983-997.

T.Krell, J. Maclean, D.J. Boam, A. Cooper, M. Resmini, K. Brocklehurst, S.M. Kelly, N.C.Price, A.J. Lapthorn & J.R. Coggins. (2001) Biochemical and X-ray crystallographic studies on shikimate kinase: The important structural role of the P-loop lysine. Protein Science 10, 1137-1149.

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