PDB 4H1Q deposited: 2012-09-11 modified: 2013-05-01
Title Crystal structure of mutant MMP-9 catalytic domain in complex with a twin inhibitor.
Authors Antoni, C., Beau, F., Costa, B., Da Pozzo, E., Devel, L., Dive, V., Giacomelli, C., Martini, C., Nencetti, S., Nuti, E., Orlandini, E., Rosalia, L., Rossello, A., Stura, E.A., Vera, L.
Structure factors resolution 1.59 rfactor 0.17 rfree 0.211
DPI 0.21 theoretical min: 0.10
Related PDB Entries 4H2E 4H30 4H3X 4H49 4H76 4H84 4HMA 4I03

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.

J.Struct.Biol. 2013 Jun; 182(3):246-254 doi:10.1016/j.jsb.2013.03.015

Cross References
Database source Identifier Description
PubMed 23567804 JSBIEM
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4H1Q/1 4H1Q 1 monomer 0 1 7 1399
4H1Q/2 4H1Q 2 monomer 0 1 6 1431