Matrix metalloproteinase–inhibitor interaction: the solution structure of the catalytic domain of human matrix metalloproteinase-3 with different inhibitors |
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Authors: | Luis A Alcaraz Lucia Banci Ivano Bertini Francesca Cantini Antonio Donaire Leonardo Gonnelli |
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Institution: | (1) Magnetic Resonance Center (CERM), University of Florence, Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy;(2) Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, Edificio Torregaitan, Elche, Alicante, Spain;(3) Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy;(4) Department of Inorganic Chemistry, Universidad de Murcia, Campus Universitario de Espinardo, Apdo. 4021, 30071 Murcia, Spain |
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Abstract: | We structurally characterized the adducts of the catalytic domain of matrix metalloproteinase-3 (MMP3) with three different
nonpeptidic inhibitors by solving the solution structure of one adduct MMP3–N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid] and then by calculating structural models of the other two adducts using
a reduced set of experimental NMR data, following a recently proposed procedure (Bertini et al. in J. Med. Chem. 48:7544–7559, 2005). The inhibitors were selected with the criteria of maintaining in all of them the same zinc-coordinating
moiety and of selectively changing the substituents and/or the functional groups. The backbone dynamics on various time scales
have been characterized as well. The comparison among these structures and with others previously reported allowed us to elucidate
fine details of inhibitor–receptor interactions and to develop some criteria, which could guide in optimizing the design of
selective inhibitors.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | NMR Solution structure Drug discovery Protein– ligand interaction Docking |
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