Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.640488
Title: Ligand design for two proteins of therapeutic relevance
Author: Anderson, Violet R.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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Abstract:
Elastase is irreversibly inhibited by compounds incorporating a β-lactam ring and this thesis describes structural studies on three classes of β-lactam inhibitor. The mechanism of inhibition begins with nucleophilic attack by the catalytic serine on the carbonyl which is at position 2 of all the β-lactams. In all cases this results in the opening of the ring between position one and two and the departure of the position four substituents. X-ray crystal structures and mass spectra obtained of elastase in complex with each of the ligands described the bound products of each reaction. β-lactams having geminal diethyl groups at position 3 of the ring were proven to react by a different mechanism to those with a hydroxyl ethyl at position 3. Hydroxy ethyl ligands are proposed to result in amore stable bound product. A ligand which had an ethyl group attached by a double bond at position 3 was found to be hydrolysed by the enzyme to give a breakdown product which remains non-covalently bound in the active site. A crystal structure of the non-covalently bound product was determined. The determination of 3-D structures of elastase with gold triethyl-phosphine and rhenate is also reported. Factor XIII is the last enzyme in the blood coagulation cascade, stabilising blood clots by cross-linking fibrin. It is a transglutaminase, linking a lysine from one peptide substrate to a glutamine from the other via e(γ-glutamyl)lysyl isopeptide bonds. In plasma, factor XIII exists in the inactive form as a heterotetramer, having two A subunits and two B subunits. Upon activation the two B subunits fall away and the A-A dimer performs the catalysis. The activation process also involves an unknown conformational change and thrombin cleavage which allows the departure of an activation peptide. Attempts made to purify the active form of the enzyme for crystallisation are described. A crystal structure of the inactive form of factor XIII has been used as the basis for computer modelling of the interaction of peptide ligands and the active form of the enzyme.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.640488  DOI: Not available
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