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Prof Jonathan Cooper
Laboratory for Protein Crystallography, Centre for Amyloidosis and Acute Phase Proteins
UCL Division of Medicine (Royal Free Campus)
Tel: 0207 433 2737
Fax: 0207 433 2803
Prof Jonathan Cooper profile picture
  • Emeritus Professor of Structural Biology
  • Div of Medicine
  • Faculty of Medical Sciences
Research Groups
Research Themes
Research Summary
Neuronal signalling proteins. We solved the first crystal structure of the neuronal calcium-sensor protein calexcitin which is up-regulated following Pavlovian conditioning and is implicated in neuronal excitation and plasticity. Calexcitin is known to regulate potassium channels and the ryanodine receptor. Our recently determined three-dimensional structure of calexcitin is being used as the basis for analysing how the structure changes at different calcium ion concentrations that correspond with the different physiological states of neurons. We are analysing site-directed mutants of calexcitin designed to investigate the roles of its calcium-binding sites. This and other related projects are conducted in collaboration with Dr V. O'Connor (University of Southampton).

Tetrapyrrole biosynthesis enzymes. One main focus of my research is on enzymes involved in tetrapyrrole biosynthesis. These include 5-aminolaevulinate dehydratase (ALAD) which catalyses the formation of a pyrrole (porphobilinogen) from two molecules of 5-aminolaevulinic acid. We are also analysing the subsequent enzyme in the pathway namely porphobilinogen deaminase (PBGD) which catalyses the condensation of four molecules of porphobilinogen to give a linear tetrapyrrole. The structures of these two enzymes from different species, including humans, have been solved to analyse the mechanism of action and, in the case of ALAD, the basis for its metal ion specificity (in collaboration with Prof. P.M. Shoolingin-Jordan, Southampton and Prof. M.J. Warren, Kent). We have also analysed the bound structures of a number of inhibitors which has improved our understanding of the catalytic mechanism. Our high-resolution structure of ALAD co-crystallised with substrate possessed a bound pyrrole-like product or intermediate covalently bound at the active site. Hereditary deficiencies in these enzymes give rise to a range of diseases known as porphyrias and our structures provided the first molecular insight into the effects of these mutations on the enzymes.

C-C bond hydrolases. MhpC is a C-C bond hydrolase involved in the bacterial degradation of phenylpropionic acid. MhpC may have potential in biotransformation reactions. The enzyme is also of interest in terms of engineering organisms capable of removing persistent toxic compounds from the environment. Our structure of the enzyme, solved at high resolution along with structures of various bound inhibitors, site-directed mutants and a product complex of an inactive mutant, have shed much light on the mechanism. More recently we have determined the structure of a related enzyme which acts on an aromatic substrate by a similar mechanism.

Inositol monophosphatase (IMPase). The enzyme inositol monophosphatase is involved in the recycling of inositol from inositol polyphosphate secondary messengers. The enzyme is believed to be the main target for the manic depression drug lithium and our objective is to define the binding site for this drug as a basis for designing improved inhibitors. We have solved the X-ray structure of recombinant bovine inositol monophosphatase at 1.4 Å resolution (in collaboration with Prof. M. Gore, Southampton).

Aspartic proteinases. We have analysed the structures of aspartic proteinase inhibitor complexes, mainly concentrating on the fungal enzyme endothiapepsin since we have found this to be remarkably suited for study by atomic resolution X ray and neutron diffraction analysis as well as NMR. The aspartic proteinases are a family of enzymes involved in a number of important physiological and pathological processes such as hypertension, amyloidosis and HIV infection. This work is done in collaboration with Prof. L. Coates (Oak Ridge National Laboratory) and is providing data of significant importance for understanding the catalytic mechanism of this class of proteinase.

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