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Phosphate Processing in Enzymes: Structure, Dynamics and Chemistry

Objective

Phosphate ester hydrolysis is one of the most important classes of chemical reactions in biology, playing a central role in nucleic acid processing, energy transduction, and signalling. Despite the importance of this ubiquitous reaction, the mechanistic details of phosphate ester cleavage remain obscure due to the complex nature of the reaction. In addition, there is an active debate concerning possible reaction intermediates. Here we aim to clarify the molecular basis of this enzymatic mechanism by studying P-O bond cleavage by Nucleoside Triphosphate (NTP) - processing enzymes and by the HIV-RT system. Hydrolysis of NTP represents a biochemical reaction essential in most processes of life: energy storage and transfer, replication of the genetic material, translation, regulation, etc. We will clarify the roles of metal ions in NTP enzymes and the ubiquitous arginine finger-type interaction occurring during the catalytic process. Phosphate hydrolysis is also catalysed by the HIV-RT enzyme. HIV-RT is a main drug target for AIDS disease. Unfortunately, current HIV drugs cannot cure the disease, forcing patients to remain on viral suppressant medications indefinitely. The major emerging problem with the current HIV viral drugs is the acquired drug resistance. To combat this problem, it is essential to design new drugs that target alternative functions and binding sites. More than half of the current HIV drugs target the HIV-RT reverse transcriptase function. Nevertheless, HIV-RT also carries out an RNase H function that is essential to viral replication. Here, we aim to obtain detailed information on the conformational flexibility and tautomerism of the inhibitors and to find the link between these properties and the potency and selectivity of the RNase function inhibitors. By exploring the flexibility of the inhibitors as well as mutations in the protein, we also aim to identify how drug resistant mutants may emerge as a result of drug therapies.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/nucleic acid
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/pharmaceutical drug
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

FP7-PEOPLE-2013-IEF
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

KING'S COLLEGE LONDON
Address
Strand
WC2R 2LS London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 309 235,20
Administrative Contact
Paul Labbett (Mr.)