PDB 4L2L deposited: 2013-06-04 modified: 2014-04-23
Title Human Leukotriene A4 Hydrolase complexed with ligand 4-(4-benzylphenyl)thiazol-2-amine
Authors Haeggstrom, J.Z., Kleinschmidt, T., Olsson, U., Rinaldo-Matthis, A., Rutishauser, D., Samuelsson, B., Stsiapanava, A., Wan, M., Zubarev, R.A.
Structure factors resolution 1.648 rfactor 0.14171 rfree 0.17514
DPI 0.17 theoretical min: 0.09
Related PDB Entries 4MKT 4MS6

Leukotriene (LT) A4 hydrolase/aminopeptidase (LTA4H) is a bifunctional zinc metalloenzyme that catalyzes the committed step in the formation of the proinflammatory mediator LTB4. Recently, the chemotactic tripeptide Pro-Gly-Pro was identified as an endogenous aminopeptidase substrate for LTA4 hydrolase. Here, we determined the crystal structure of LTA4 hydrolase in complex with a Pro-Gly-Pro analog at 1.72 Å. From the structure, which includes the catalytic water, and mass spectrometric analysis of enzymatic hydrolysis products of Pro-Gly-Pro, it could be inferred that LTA4 hydrolase cleaves at the N terminus of the palindromic tripeptide. Furthermore, we designed a small molecule, 4-(4-benzylphenyl)thiazol-2-amine, denoted ARM1, that inhibits LTB4 synthesis in human neutrophils (IC50 of ∼0.5 μM) and conversion of LTA4 into LTB4 by purified LTA4H with a Ki of 2.3 μM. In contrast, 50- to 100-fold higher concentrations of ARM1 did not significantly affect hydrolysis of Pro-Gly-Pro. A 1.62-Å crystal structure of LTA4 hydrolase in a dual complex with ARM1 and the Pro-Gly-Pro analog revealed that ARM1 binds in the hydrophobic pocket that accommodates the ω-end of LTA4, distant from the aminopeptidase active site, thus providing a molecular basis for its inhibitory profile. Hence, ARM1 selectively blocks conversion of LTA4 into LTB4, although sparing the enzyme's anti-inflammatory aminopeptidase activity (i.e., degradation and inactivation of Pro-Gly-Pro). ARM1 represents a new class of LTA4 hydrolase inhibitor that holds promise for improved anti-inflammatory properties.

Proc.Natl.Acad.Sci.USA 2014 Mar; 111(11):4227-4232 doi:10.1073/pnas.1402136111

Cross References
Database source Identifier Description
PubMed 24591641 PNASA6
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4L2L/0 4L2L 0 monomer 0 1 9 4838