On the Affinity Regulation of the Metal-Ion-Dependent Adhesion Sites in Integrins.
Density functional theory and a polarizable continuum model are used to (i) understand the affinity modulating mechanisms of the interaction between the metal-ion-dependent adhesion site (MIDAS) of a selected integrin, lymphocyte function-associated antigen-1 (LFA-1) and a ligand mimetic acetate mol...
| Published in: | Journal of the American Chemical Society Vol. 128; no. 11; pp. 3554 - 3564 |
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| Main Authors: | , , , , , |
| Format: | Article |
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American Chemical Society
3/22/2006
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| Subjects: | |
| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=20426139&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 20426139 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 3/22/2006 vid: 128 iid: 11 pid: 997 pub: American Chemical Society artinfo: ui: 20426139 10.1021/ja054142a ppf: 3554 ppct: 10 formats: tig: atl: On the Affinity Regulation of the Metal-Ion-Dependent Adhesion Sites in Integrins. aug: au: San Sebastian, Eider Mercero, Jose M. Stote, Roland H. Dejaegere, Annick Cossio, Fernando P. Lopez, Xabier affil: Kimika Fakultatea, Euskal Herriko Unibertsitatea and Donostia International Physics Center (DIPC), P. K. 1072, 20080 Donostia, Spain Laboratoire de Biophysicochimie Moléculaire, UMR Chimie Physique Moléculaire et Spectroscopie, Université Louis Pasteur, Strasbourg, France UMR 7104 Biocomputing Group, Structural Biology & Genomics Department, Ecole Supérieure de Biotechnologie de Srrasbourg-IGBMC, BP 10413 - F- 67412 Illkirch, France su: Integrins Density functionals Metal ions Ligands (Chemistry) Carboxylic acids Adhesion sug: subj: Integrins Density functionals Metal ions Ligands (Chemistry) Carboxylic acids Adhesion ab: Density functional theory and a polarizable continuum model are used to (i) understand the affinity modulating mechanisms of the interaction between the metal-ion-dependent adhesion site (MIDAS) of a selected integrin, lymphocyte function-associated antigen-1 (LFA-1) and a ligand mimetic acetate molecule and to (ii) propose a new, promising family of inhibitors to block the interaction of the integrin with intercellular adhesion molecule-1 (ICAM-1). We quantify the effect of isolated factors, such as the metal coordination, the nature of the ligand or the cation present on the MIDAS, and the effect of the permittivity of the media. We show that the affinity for ligand decreases when metal coordination changes from the open conformation to the closed conformation. In addition, Mn and Zn showed to be good competitors for the octahedrically coordinated Mg and yielded excellent affinity values, whereas Ca in an octahedric environmet would decrease the affinity for the ligand. Our affinity studies of the open MIDAS showed that nitronate-derived or carboxylic acid-containing ligands may represent new promising scaffolds of future inhibitors. Finally, we show that affinities are always highly favored by low-dielectric environments, which explains the propensity of MIDAS motifs to be surrounded by hydrophobic residues in integrins and highlights the importance of including hydrophobic groups in the inhibitors. pubtype: Academic Journal doctype: Article src: R language: English refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2006 holdings: @attributes: islocal: N |
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