4H76

Crystal structure of the catalytic domain of Human MMP12 in complex with a broad spectrum hydroxamate inhibitor

Summary for 4H76

• Entry DOI: 10.2210/pdb4h76/pdb
• Related: 1RMZ 3LIK 3LIL 3LJG 3TS4 3TSK 4EFS 4GQL 4GR0 4H30 4H3X
• Descriptor: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (8 entities in total)
• Functional Keywords: broad spectrum mmp hydroxamate inhibitor, metzincin, zinc protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P39900
• Total number of polymer chains: 1
• Total formula weight: 18869.87

Authors

Stura, E.A.,Vera, L.,Cassar-Lajeunesse, E.,Nuti, E.,Dive, V.,Rossello, A. (deposition date: 2012-09-20, release date: 2013-04-24, Last modification date: 2023-09-20)

Primary citation

Antoni, C.,Vera, L.,Devel, L.,Catalani, M.P.,Czarny, B.,Cassar-Lajeunesse, E.,Nuti, E.,Rossello, A.,Dive, V.,Stura, E.A.
Crystallization of bi-functional ligand protein complexes.
J.Struct.Biol., 182:246-254, 2013

PubMed 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.

PubMed: 23567804
DOI: 10.1016/j.jsb.2013.03.015

Experimental method

X-RAY DIFFRACTION (1.5 Å)