Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Reexamination Certificate
1998-05-10
2001-03-06
Hobbs, Lisa J. (Department: 1652)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S183000, C514S012200, C702S019000, C702S022000
Reexamination Certificate
active
06197495
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to the identification of a novel enzyme active site and methods enabling the design and selection of inhibitors of that active site.
1. Background of the Invention
Transfer RNA (tRNA) synthetase enzymes are of interest as potential targets for antibacterial agents. Mupirocin, a selective inhibitor of bacterial isoleucyl tRNA synthetase, is marketed for the treatment of skin infections and the eradication of nasal carriage of MRSA (methicillin-resistant
Staphylococcus aureus
) in hospital staff and patients.
Glycyl tRNA synthetase, a class I enzyme, is unusual in that its oligomeric structure varies depending on the organism from which it was isolated. Nucleic acid and amino acid sequences for glycyl tRNA synthetases are publicly available, including those of
Thermus thermophilus, Mycoplasma genitalium, Homo sapiens,
yeast,
Boinbyx mori
and
Caenorhabditis elegans,
which are all characterized by a2 dimers, and
Coxiella burnetti, Escherichia coli, Chlamydia trachomatous, Neisseria gonorrheae,
Synechocystis sp., and
Haemophilus influezae
, which are all characterized by being a2b2 tetramers.
There is a need in the art for novel tRNA synthetase enzyme active sites and catalytic sequences to enable identification and structure-based design of synthetase inhibitors, which are useful in the treatment or prophylaxis of diseases, particularly bacterial diseases caused by bacteria of the genus Staphylococcus, as well as other bacteria which may share catalytic domains with those of the genus Staphylococcus.
2. Summart of the Invention
In one aspect, the present invention provides a novel
Staphylococcis aureus
tRNA synthetase enzyme active site crystalline form.
In still another aspect, the present invention provides a novel tRNA synthetase composition characterized by a catalytic site of 16 amino acid residues.
In yet another aspect, the invention provides a method for identifying inhibitors of the compositions described above which methods involve the steps of: providing the coordinates of the tRNA synthetase structure of the invention to a computerized modeling system; identifying compounds which will bind to the structure; and screening the compounds identified for tRNA synthetase inhibitory bioactivity.
In a further aspect, the present invention provides an inhibitor of the catalytic activity of any composition bearing the catalytic domain described above.
Another aspect of this invention includes machine readable media encoded with data representing the coordinates of the three-dimensional structure of the tRNA synthetase crystal.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
REFERENCES:
Niyomporng et al., “Biosynthesis of the Peptidoglycan of Bacterial Cell Walls”,J. Biol. Chem., vol. 243, No. 4, pp. 773-778 ,(1968).
Niyomporn, et al., “Glycyl-tRNA Synthetase (Staphylococcus aureus)”,Meth. Enzymol., vol. 17, pp. 966-970, (1971).
Belrhali, et al., “Crystal Structures at 2.5 Angstrom Resolution of Seryl-tRNA Synthetase Complexed with two Analogs of Seryl Adenylate”,Science, vol. 263(5152), pp. 1432-1436, (1994).
Ueda, et al., “X-ray Crystallographic Conformational Study of 5′-O-[N-(L-alanyl)-sulfamoyl]adenosine, A Substrate Analog for Alanyl-tRNA Synthetase.”,Biochim. Biophys. Acta, vol. 1080(2), pp. 126-134, (1991).
Logan, et al., “Crystal Structure of Glycyl-tRNA Synthetase from Thermus Thermophilus”,EMBO J., vol. 17(17), pp. 4156-4167, (1995).
Janson Cheryl A.
Osborne Neal Frederick
Qiu Xiayang
Richardson Christine Mary
Gimmi Edward R.
Hobbs Lisa J.
King William T.
Kinzig Charles M.
SmithKline Beecham Corporation
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