Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599439
Title: Structural and biochemical studies of inhibitors of ATP synthase
Author: Gledhill, J. R.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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Abstract:
The X-ray crystallographic structures of the inhibited F1-ATPase in complex with the dietary phyto-polyphenols resveratrol, piceatannol and quercetin have been determined and they illuminate their mechanism of inhibition. These inhibitors bind to a unique inhibitory site in the collar region of F1-ATPase in a hydrophobic pocket formed between one of the catalytic β-subunits and the C-terminal region of the γ-subunit, which forms part of the rotor. They act by preventing the rotation of the γ-subunit during catalysis. These results show that this inhibitory site can accommodate a number of phyto-polyphenols and their derivatives. They also emphasise the importance of the conserved C-terminal region of the γ-subunit in the active enzyme. The existing structural model of the dimeric F1-IF1 complex was poorly defined in the interacting regions. Therefore, a monomeric but active fragment of the inhibitor protein IF1 (I1-60), which lacks the dimerisation domain has been used to form a monomeric inhibited complex that has been analysed to high resolution by X-ray crystallography. All the interacting regions between the F1-ATPase and IF1 have been resolved and it has been shown that the existing structural model is incorrect. The nucleotide occupancy of the new structure differs from that in the dimeric F1-IF1 structure and it represents the final “dead-end” complex with ADP bound to the catalytic sites. These studies have furthered our understanding of the regulation of ATP synthase and represent steps towards the use of F1 inhibitors in a therapeutic context.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.599439  DOI: Not available
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