Poster #RP229
STRUCTURAL MODEL FOR ALPHA6BETA1 INTEGRIN AND DYNAMICS OF INTERACTION WITH SMALL ECD BASED LIGANDS.
Aline Rossi Silveira*, Jorge Hernandez Fernandez*, Ernesto Caffarena**, Wilson Savino**, Ana Tereza Ribeiro Vasconcelos*
*LNCC-Laboratório Nacional de Computação Científica, Petrópolis, Brazil; **Fiocruz-Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Integrins are transmembrane adhesion receptors that mediate dynamic linkages between intracellular cytoskeleton and the extracellular matrix. Formed by combination of different alpha and beta subunits, integrins are involved in cell adhesion, migration and outside-in/inside-out signaling. We use sequential and structural alignments of alpha and beta integrin subunits to obtain a general structural profile for the beta-propeller and A-domain in lacking I-Domain integrins, and molecular modeling and dynamics to obtain a detailed interaction model of alpha6beta1 and alphaIIbbeta3 in complex with antagonists based in small ECD or RGD peptide structures. The conserved Mg2+ containing MIDAS site in the A-domain always interacts with the negative C-terminal residues of RGD or ECD based antagonists. Despite the structural homogeneity of the integrin A-domain, the beta-propeller domain show length heterogeneity in loops between blades 3 and 4. Human alpha6 and alpha7 integrins contains an insertion in these loops in two alpha6 and one alpha7 isoforms and structural alignment shows these loops as the putative ligand-binding motif for the N-terminal residues of integrin antagonists. In molecular dynamic experiments, N-terminal Glu or Arg residues from ECD and RGD based antagonists showed cross-exclusive electrostatic interactions with the same heterogeneous region, suggesting these loops as important structures in ligand recognition and discrimination.
Funded by CNPq/MCT/Capes.