spacer Crystal structure of the catalytic domain of Human MMP12 in complex with a broad spectrum hydroxamate inhibitor
Primary citation
Title Powerful twin carboxylic inhibitors for MMP homodimerisation.
Authors Nuti,; Antoni,; Vera,; L.,; Beau,; Da Pozzo,; Costa,; Giacomelli,; E., Orlandinisearch; Nencetti,; L., Rosaliasearch; Dive,; Stura,; Martini,; A., Rossellosearch
Journal To be Published
Secondary citations
Title Crystallization of bi-functional ligand protein complexes.
Authors Antoni,; Vera,; Devel,; Catalani,; Czarny,; Cassar-Lajeunesse,; Nuti,; Rossello,; Dive,; Stura,
Journal vol:12, pag:2441-2450 (2013), Identifiers: PubMed ID (23567804)search DOI (10.1016/j.jsb.2013.03.015)
Abstract Homodimerization is important in signal transduction and can play a crucial role in many other biological systems. To obtaining structural information for the design of molecules able to control the signalization pathways, the proteins involved will have to be crystallized in complex with ligands that induce dimerization. Bi-functional drugs have been generated by linking two ligands together chemically and the relative crystallizability of complexes with mono-functional and bi-functional ligands has been evaluated. There are problems associated with crystallization with such ligands, but overall, the advantages appear to be greater than the drawbacks. The study involves two matrix metalloproteinases, MMP-12 and MMP-9. Using flexible and rigid linkers we show that it is possible to control the crystal packing and that by changing the ligand-enzyme stoichiometric ratio, one can toggle between having one bi-functional ligand binding to two enzymes and having the same ligand bound to each enzyme. The nature of linker and its point of attachment on the ligand can be varied to aid crystallization, and such variations can also provide valuable structural information about the interactions made by the linker with the protein. We report here the crystallization and structure determination of seven ligand-dimerized complexes. These results suggest that the use of bi-functional drugs can be extended beyond the realm of protein dimerization to include all drug design projects.
MeSH terms
Title New N-arylsulfonyl-N-alkoxyaminoacetohydroxamic acids as selective inhibitors of gelatinase A (MMP-2).
Authors Rossello,; Nuti,; Orlandini,; Carelli,; Rapposelli,; Macchia,; Minutolo,; Carbonaro,; Albini,; Benelli,; Cercignani,; Murphy,; Balsamo,
Journal vol:12, pag:2441-2450 (2004), Identifiers: PubMed ID (15080939)search DOI (10.1016/j.bmc.2004.01.047)
Abstract New N-arylsulfonyl-substituted alkoxyaminoaceto hydroxamic acid derivatives of types 8 and 10 designed as oxa-analogues of known sulfonamide-based MMPi of types 2 and 7 were synthesized and tested for their inhibitory activities on some matrix metalloproteinases. The combination of a biphenylsulfonamide group with oxyamino oxygen in the pharmacophoric central skeleton of sulfonamide-based MMPi obtained in the new sulfonamides 10 seems to be able to give selectivity for MMP-2 over MMP-1. The most potent derivative of this type, 10a, shows similar anti-invasive properties to the analogue reference drug CGS27023A, 2, in an in vitro model of invasion on matrigel, carried out on cellular lines of fibrosarcoma HT1080 (tumoural cells over-expressing MMP-2 and MMP-9).
MeSH terms Cell Linesearch, Tumorsearch, Enzyme Inhibitorssearch, Humanssearch, Hydroxamic Acidssearch, Magnetic Resonance Spectroscopysearch, Matrix Metalloproteinase 2search, Matrix Metalloproteinase Inhibitorssearch, Protease Inhibitorssearch