Obiettivo DNA topoisomerases (topos) are an essential part of the human cell's replication, transcription and recombination machinery. The discovery that topos are the intracellular targets for a wide variety of known and emerging antitumour drugs, appear to be among the most important discoveries in cancer research over the last decades. Further development of cancer chemotherapies will be dramatically aided by a fundamental understanding of the structural basis of the topos function and the elucidation of the molecular mechanism of how the antitumour drugs intervene to poison these enzymes.The project will research both the structural basis of the topos enzymatic mechanism and the alterations in enzymes structure and dynamics upon drug binding. In addition, we will examine the impact of the topos on the structure of the bound drug. This information will be used to determine the unique chemical structural determinants of the drugs that productively interact with the topos to poison their function. The results will guide us in design, synthesis and studies of new topos poisons with improved therapeutic indexes.The research aims to:- Identify the topos I and II amino acids active in recognition and high affinity binding of the enzymes to appropriate DNA duplex sequences;- Examine the molecular structural basis for both the covalent attachment of catalytically active topos to the DNA and for its subsequent release from the DNA;- Determine the molecular mechanism of the topos I (II)-mediated DNA single- (double-) strand cleavage and the subsequent DNA single- (double-) strand transfer reaction;- Examine the intermolecular interactions within the so-called "ternary cleavable complexes" between the drugs, topos and their DNA substrate;- Elucidate the structural basis of the mechanism by which antitumour drugs, topos I and/or II inhibitors, affect the enzymes function;- Basing on the structural information obtained in research, to design, synthesise and test with the traditional biochemical and state-of-the art spectroscopic techniques the topos I and/or II poisons with improved therapeutic indexes.The specific aims will be achieved in a co-ordinated program involving four applicants from four INTAS-member countries and five applicants from three NIS countries. Each team has specific experience in biochemistry, molecular biology, biophysics, immunochemistry, protein chemistry, molecular modelling, biosynthesis or state-of-the art spectroscopic techniques applied to the studies of the enzymes and supra-molecular complexes. Six from the nine involved teams just have an experience of efficient co-operation. Programma(i) IC-INTAS - International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993- Argomento(i) 4 - Life Sciences INTAS - INTAS Invito a presentare proposte Data not available Meccanismo di finanziamento Data not available Coordinatore Universite de Reims Champagne-Ardennes Contributo UE Nessun dato Indirizzo 51, rue Cognacq Jay 51100 Reims Francia Mostra sulla mappa Costo totale Nessun dato Partecipanti (8) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto Institute of Plant Physiology and Biochemistry Russia Contributo UE Nessun dato Indirizzo 132 Lermontov Street 664033 Irkutsk Mostra sulla mappa Costo totale Nessun dato National Academy of Sciences of Ukraine Ucraina Contributo UE Nessun dato Indirizzo 150 Zabolotny str. 03143 Kiev Mostra sulla mappa Costo totale Nessun dato National Technological University of Athens Grecia Contributo UE Nessun dato Indirizzo Zografou Campus 15780 Athens Mostra sulla mappa Costo totale Nessun dato Russian Academy of Sciences Russia Contributo UE Nessun dato Indirizzo 32 Vavilov Street 117984 Moscow Mostra sulla mappa Costo totale Nessun dato Russian Academy of Sciences Russia Contributo UE Nessun dato Indirizzo 16/10 Miklukho-Maklaya 117871 Moscow Mostra sulla mappa Costo totale Nessun dato UNIVERSITY OF YORK Regno Unito Contributo UE Nessun dato Indirizzo University Road YO1 5DD YORK Mostra sulla mappa Costo totale Nessun dato University of Bologna Italia Contributo UE Nessun dato Indirizzo via Irnerio 48 40126 Bologna Mostra sulla mappa Costo totale Nessun dato Yanka Kupala State University of Grodno Bielorussia Contributo UE Nessun dato Indirizzo Ozheshko str., 22 230023 Grodno Mostra sulla mappa Costo totale Nessun dato
