PDB 3RTS deposited: 2011-05-04 modified: 2012-07-04
Title Human MMP-12 catalytic domain in complex with*N*-Hydroxy-2-(2-phenylethylsulfonamido)acetamide
Authors Calderone, V., Fragai, M., Luchinat, C., Massaro, A., Mordini, A., Mori, M.
Structure factors resolution 1.81 rfactor 0.16976 rfree 0.23595
DPI 0.45 theoretical min: 0.15
Related PDB Entries 3F15 3F16 3F17 3F18 3F19 3F1A 3LK8 3N2U 3N2V 3NX7 3RTT 4GUY

By solving high-resolution crystal structures of a large number (14 in this case) of adducts of matrix metalloproteinase 12 (MMP12) with strong, nanomolar, inhibitors all derived from a single ligand scaffold, it is shown that the energetics of the ligand-protein interactions can be accounted for directly from the structures to a level of detail that allows us to rationalize for the differential binding affinity between pairs of closely related ligands. In each case, variations in binding affinities can be traced back to slight improvements or worsening of specific interactions with the protein of one or more ligand atoms. Isothermal calorimetry measurements show that the binding of this class of MMP inhibitors is largely enthalpy driven, but a favorable entropic contribution is always present. The binding enthalpy of acetohydroxamic acid (AHA), the prototype zinc-binding group in MMP drug discovery, has been also accurately measured. In principle, this research permits the planning of either improved inhibitors, or inhibitors with improved selectivity for one or another MMP. The present analysis is applicable to any drug target for which structural information on adducts with a series of homologous ligands can be obtained, while structural information obtained from in silico docking is probably not accurate enough for this type of study.

J.Am.Chem.Soc. 2007 Mar; 129(9):2466-2475 doi:10.1021/ja065156z

Cross References
Database source Identifier Description
PubMed 17269766 JACSAT
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3RTS/0 3RTS 0 monomer 0 1 6 1292