5I12

Crystal structure of the catalytic domain of MMP-9 in complex with a selective sugar-conjugated arylsulfonamide carboxylate water-soluble inhibitor (DC27).

Summary for 5I12

• Entry DOI: 10.2210/pdb5i12/pdb
• Related: 4HMA 5IOL
• Descriptor: Matrix metalloproteinase-9,Matrix metalloproteinase-9, ZINC ION, CALCIUM ION, ... (8 entities in total)
• Functional Keywords: inhibitor, complex, glycoconjugate, metalloprotease, hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted, extracellular space, extracellular matrix : P14780
• Total number of polymer chains: 1
• Total formula weight: 18817.71

Authors

Stura, E.A.,Rosalia, L.,Cuffaro, D.,Tepshi, L.,Ciccone, L.,Rossello, A. (deposition date: 2016-02-05, release date: 2016-07-06, Last modification date: 2024-01-10)

Primary citation

Nuti, E.,Cuffaro, D.,D'Andrea, F.,Rosalia, L.,Tepshi, L.,Fabbi, M.,Carbotti, G.,Ferrini, S.,Santamaria, S.,Camodeca, C.,Ciccone, L.,Orlandini, E.,Nencetti, S.,Stura, E.A.,Dive, V.,Rossello, A.
Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors.
Chemmedchem, 11:1626-1637, 2016

PubMed Abstract: Matrix metalloproteinase-12 (MMP-12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β-N-acetyl-d-glucosamine moiety, were designed and synthesized as MMP-12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP-12 inhibitor with improved water solubility, compound 3 [(R)-2-(N-(2-(3-(2-acetamido-2-deoxy-β-d-glucopyranosyl)thioureido)ethyl)biphenyl-4-ylsulfonamido)-3-methylbutanoic acid], was identified.

PubMed: 27356908
DOI: 10.1002/cmdc.201600235

Experimental method

X-RAY DIFFRACTION (1.59 Å)