title: Extra binding region induced by non-zinc chelating inhibitors into the S1' subsite of matrix metalloproteinase 8 (MMP-8).
abstract: The mode of binding and the activity of the first two non-zinc chelating, potent, and selective inhibitors of human neutrophil collagenase are reported. The crystal structures of the catalytic domain of MMP-8, respectively complexed with each inhibitor, reveals that both ligands are deeply inserted into the primary specificity subsite S(1)', where they induce a similar conformational change of the surrounding loop that is endowed with the main specificity determinants of MMPs. Accord to this rearrangement, both inhibitors remove the floor of the pocket formed by the Y227 side-chain, rendering available an extra binding region never explored before. The present data show that potent and more selective inhibitors can be obtained by developing ligands able to interact with the selectivity regions of the enzyme rather than with the catalytic zinc ion, which is the common feature of all MMP members.
authors.affiliation: Istituto di Cristallografia-CNR, Area della Ricerca Roma 1, Via Salaria Km.29,300, I-00016 Monterotondo Stazione, Roma, Italy. giorgio.pochetti@ic.cnr.it
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pochetti
authors.forename: Roberta
authors.initials: R
authors.lastname: Montanari
authors.forename: Christian
authors.initials: C
authors.lastname: Gege
authors.forename: Carine
authors.initials: C
authors.lastname: Chevrier
authors.forename: Arthur G
authors.initials: AG
authors.lastname: Taveras
authors.forename: Fernando
authors.initials: F
authors.lastname: Mazza
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020784:Matrix Metalloproteinase 8