On the affinity regulation of the metal-ion-dependent adhesion sites in integrins

Journal of the American Chemical Society
Eider San SebastianXabier Lopez

Abstract

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, Mn2+ and Zn2+ showed to be good competitors for the octahedrically coordinated Mg2+ and yielded excellent affinity values, whereas Ca2+ in an octahedric environment 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 environ...Continue Reading

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Citations

Aug 1, 2012·The Journal of Biological Chemistry·Paul H WeinrebVirgil L Woods
Feb 28, 2009·Blood Cells, Molecules & Diseases·Elena LomakinaRichard E Waugh
Aug 19, 2007·Biochimica Et Biophysica Acta·Thomas Vorup-JensenTimothy A Springer
Oct 9, 2007·Journal of Molecular Biology·Thomas GaillardRoland H Stote
Apr 4, 2015·Biochimica Et Biophysica Acta·Eva KläningThomas Vorup-Jensen
Jul 7, 2017·Chemical Communications : Chem Comm·Youssef El Khoury, Petra Hellwig
Jun 15, 2018·Cancer Science·Ryota KawaharaSiro Simizu
Aug 23, 2007·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Elixabete RezabalJesus M Ugalde
Dec 12, 2018·Frontiers in Immunology·Thomas Vorup-Jensen, Rasmus Kjeldsen Jensen
May 16, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Xue-Ying WuChong-Xin Shan
Jan 24, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kristian Juul-MadsenThomas Vorup-Jensen
Jul 5, 2007·The Journal of Physical Chemistry. B·Eider San SebastianXabier Lopez
Jul 5, 2007·Inorganic Chemistry·E RezabalJ M Ugalde

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