4L2L

Human Leukotriene A4 Hydrolase complexed with ligand 4-(4-benzylphenyl)thiazol-2-amine

Summary for 4L2L

• Entry DOI: 10.2210/pdb4l2l/pdb
• Related: 3U9W 4DPR
• Descriptor: Leukotriene A-4 hydrolase, ZINC ION, 4-(4-benzylphenyl)-1,3-thiazol-2-amine, ... (6 entities in total)
• Functional Keywords: metalloprotein, hydrolase, protease, zinc binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P09960
• Total number of polymer chains: 1
• Total formula weight: 70565.03

Authors

Stsiapanava, A.,Rinaldo-Matthis, A.,Haeggstrom, J.Z. (deposition date: 2013-06-04, release date: 2014-03-12, Last modification date: 2023-09-20)

Primary citation

Stsiapanava, A.,Olsson, U.,Wan, M.,Kleinschmidt, T.,Rutishauser, D.,Zubarev, R.A.,Samuelsson, B.,Rinaldo-Matthis, A.,Haeggstrom, J.Z.
Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor.
Proc.Natl.Acad.Sci.USA, 111:4227-4232, 2014

PubMed Abstract: 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.

PubMed: 24591641
DOI: 10.1073/pnas.1402136111

Experimental method

X-RAY DIFFRACTION (1.648 Å)