1ZVX

Crystal structure of the complex between MMP-8 and a phosphonate inhibitor (R-enantiomer)

Summary for 1ZVX

• Entry DOI: 10.2210/pdb1zvx/pdb
• Related: 1ZS0
• Descriptor: Neutrophil collagenase, CALCIUM ION, ZINC ION, ... (5 entities in total)
• Functional Keywords: stereoselective inhibition, phosphonic inhibitors, hydrolase, sulfonamide junction
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasmic granule: P22894
• Total number of polymer chains: 1
• Total formula weight: 18722.12

Authors

Pochetti, G.,Gavuzzo, E.,Campestre, C.,Agamennone, M.,Tortorella, P.,Consalvi, V.,Gallina, C.,Hiller, O.,Tschesche, H.,Tucker, P.A.,Mazza, F. (deposition date: 2005-06-03, release date: 2006-05-16, Last modification date: 2023-08-23)

Primary citation

Pochetti, G.,Gavuzzo, E.,Campestre, C.,Agamennone, M.,Tortorella, P.,Consalvi, V.,Gallina, C.,Hiller, O.,Tschesche, H.,Tucker, P.A.,Mazza, F.
Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates.
J.Med.Chem., 49:923-931, 2006

PubMed Abstract: Potent and selective inhibitors of matrix metalloproteinases (MMPs), a family of zinc proteases that can degrade all the components of the extracellular matrix, could be useful for treatment of diseases such as cancer and arthritis. The most potent MMP inhibitors are based on hydroxamate as zinc-binding group (ZBG). alpha-Arylsulfonylamino phosphonates incorporate a particularly favorable combination of phosphonate as ZBG and arylsulfonylamino backbone so that their affinity exceptionally attains the nanomolar strength frequently observed for hydroxamate analogues. The detailed mode of binding of [1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonate has been clarified by the crystal structures of the complexes that the R- and S-enantiomers respectively form with MMP-8. The reasons for the preferential MMP-8 inhibition by the R-phosphonate are underlined and the differences in the mode of binding of analogous alpha-arylsulfonylamino hydroxamates and carboxylates are discussed.

PubMed: 16451058
DOI: 10.1021/jm050787+

Experimental method

X-RAY DIFFRACTION (1.87 Å)