tailieunhanh - Báo cáo khoa học: Structural flexibility in Trypanosoma brucei enolase revealed by X-ray crystallography and molecular dynamics

Enolase is a validated drug target inTrypanosoma brucei. To better charac-terize its properties and guide drug design efforts, we have determined six new crystal structures of the enzyme, in various ligation states and confor-mations, and have carried out complementary molecular dynamics simula-tions. | ỊFEBS Journal Structural flexibility in Trypanosoma brucei enolase revealed by X-ray crystallography and molecular dynamics Marcos V. de A. S. Navarro1 Sandra M. Gomes Dias1 Luciane V. Mello2 3 Maria T. da Silva Giotto1 Sabine Gavalda4 - Casimir Blonski4 Richard C. Garratt1 and Daniel J. Rigden2 1 Institute de Fisica de Scio Carlos Universidade de Sao Paulo Scio Carlos SP Brazil 2 Schoolof BiologicalSciences University of Liverpool UK 3 Northwest Institute for Bio-Health Informatics University of Liverpool UK 4 Groupe de Chimie Organique Biologique Universite PaulSabatier Toulouse France Keywords crystal structure drug design enolase molecular dynamics structuralflexibility Correspondence D. J. Rigden Schoolof BiologicalSciences Crown Street University of Liverpool LiverpoolL69 7ZB UK Fax 44 151 7954406 Tel 44 151 7954467 E-mail drigden@ Website http biolsci These authors contributed equally to this work TDeceased Present address tLaboratorio Nacionalde Luz Sincrotron Campinas SP Brazil Department of Molecular Medicine College of Veterinary Medicine Cornell University Ithaca NY USA -Department of Molecular Mechanisms of MycobacterialInfections Institut de Phar-macologie et de Biologie Structurale CNRS UPS UMR5089 Toulouse France Received 5 June 2007 revised 25 July 2007 accepted 3 August 2007 doi Enolase is a validated drug target in Trypanosoma brucei. To better characterize its properties and guide drug design efforts we have determined six new crystal structures of the enzyme in various ligation states and conformations and have carried out complementary molecular dynamics simulations. The results show a striking structural diversity of loops near the catalytic site for which variation can be interpreted as distinct modes of conformational variability that are explored during the molecular dynamics simulations. Our results show that sulfate may unexpectedly induce full closure of catalytic site loops .