1UTT

Crystal Structure of MMP-12 complexed to 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl-4-(4-ethoxy[1,1-biphenyl]-4-yl)-4-oxobutanoic acid

Summary for 1UTT

• Entry DOI: 10.2210/pdb1utt/pdb
• Related: 1JIZ 1JK3 1OS2 1OS9 1ROS 1UTZ
• Descriptor: MACROPHAGE METALLOELASTASE, ACETOHYDROXAMIC ACID, 2-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL) ETHYL-4-(4'-ETHOXY [1,1'-BIPHENYL]-4-YL)-4-OXOBUTANOIC ACID, ... (6 entities in total)
• Functional Keywords: macrophage metalloelastase, non-zinc chelator, mmp-12, mmp inhibitor, hydrolase, metalloprotease
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 18370.28

Authors

Morales, R.,Perrier, S.,Florent, J.M.,Beltra, J.,Dufour, S.,De Mendez, I.,Manceau, P.,Tertre, A.,Moreau, F.,Compere, D.,Dublanchet, A.C.,O'Gara, M. (deposition date: 2003-12-10, release date: 2004-12-15, Last modification date: 2023-12-13)

Primary citation

Morales, R.,Perrier, S.,Florent, J.M.,Beltra, J.,Dufour, S.,De Mendez, I.,Manceau, P.,Tertre, A.,Moreau, F.,Compere, D.,Dublanchet, A.C.,O'Gara, M.
Crystal structures of novel non-peptidic, non-zinc chelating inhibitors bound to MMP-12.
J. Mol. Biol., 341:1063-1076, 2004

PubMed Abstract: Human macrophage elastase (MMP-12) plays an important role in inflammatory processes and has been implicated in diseases such as emphysema and chronic obstructive pulmonary disease (COPD). It is therefore an attractive target for therapeutic agents. As part of a structure-based drug design programme to find new inhibitors of MMP-12, the crystal structures of the MMP-12 catalytic domain (residues 106-268) complexed to three different non-peptidic small molecule inhibitors have been determined. The structures reveal that all three ligands bind in the S1' pocket but show varying degrees of interaction with the Zn atom. The structures of the complexes with inhibitors CP-271485 and PF-00356231 reveal that their central morpholinone and thiophene rings, respectively, sit over the Zn atom at a distance of approximately 5A, locating the inhibitors halfway down the S1' pocket. In both of these structures, an acetohydroxamate anion, an artefact of the crystallisation solution, chelates the zinc atom. By contrast, the acetohydroxamate anion is displaced by the ligand in the structure of MMP-12 complexed to PD-0359601 (Bayer), a potent zinc chelating N-substituted biaryl butyric acid, used as a reference compound for crystallisation. Although a racemate was used for the crystallisation, the S enantiomer only is bound in the crystal. Important hydrophobic interactions between the inhibitors and residues from the S1' pocket are observed in all of the structures. The relative selectivity displayed by these ligands for MMP-12 over other MMP family members is discussed.

PubMed: 15289103
DOI: 10.1016/j.jmb.2004.06.039

Experimental method

X-RAY DIFFRACTION (2.2 Å)