title: Allosteric activation of human α-thrombin through exosite 2 by suramin analogs.
abstract: Thrombin is a serine protease that plays fundamental roles in hemostasis. We have recently elucidated the crystal structure of thrombin in complex with suramin, evidencing the interaction through the anion binding exosite 2. Here, we show that the activity of thrombin toward natural and synthetic substrates is enhanced by suramin as well as analogs of suramin at a low micromolar range prior to an inhibitory component at higher concentrations. Suramin analogs substituted by phenyl and chlorine instead of methyl were the most efficient in promoting allosteric activation, with an enhancement of enzymatic activity of 250% and 630% respectively. We discuss the importance of exosite 2 as a regulatory site for ligands in both the procoagulant and inhibitory scenarios.
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Ilha do Fundão, Brazil.
authors.forename: Maria Thereza
authors.initials: MT
authors.lastname: Cargnelutti
authors.forename: Adriana Fonseca
authors.initials: AF
authors.lastname: Marques
authors.forename: Daniel
authors.initials: D
authors.lastname: Esser
authors.forename: Robson Q
authors.initials: RQ
authors.lastname: Monteiro
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Luis Mauricio T R
authors.initials: LM
authors.lastname: Lima
mesh_terms: D001665:Binding Sites; D004789:Enzyme Activation; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D013237:Stereoisomerism; D013498:Suramin / Q000031:analogs & derivatives*; D013917:Thrombin / Q000737:chemistry* / Q000648:ultrastructure*
chemical_list: D013498:Suramin; D013917:Thrombin