7kze | pdb_00007kze

Substrate-dependent divergence of leukotriene A4 hydrolase aminopeptidase activity

spinqualitylabelsall models 7kze, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7kze is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.9Å Ligands: N0Y, PGE, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LKHA4_HUMAN Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity. Publication Abstract from PubMed The aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTA4H AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent reports have introduced substantial complexity disconnecting the LTA4H modulator 4-methoxydiphenylmethane (4MDM) from PGP as follows: (1) 4MDM inhibits PGP hydrolysis and subsequently inhibition of LTA4H AP activity, and (2) 4MDM activates the same enzyme target in the presence of alternative substrates. Differential modulation of LTA4H by 4MDM was probed in a murine model of acute lung inflammation, which showed that 4MDM modulates the host neutrophilic response independent of clearing PGP. X-ray crystallography showed that 4MDM and PGP bind at the zinc binding pocket and no allosteric binding was observed. We then determined that 4MDM modulation is not dependent on the allosteric binding of the ligand, but on the N-terminal side chain of the peptide. In conclusion, our study revealed that a peptidase therapeutic target can interact with its substrate and ligand in complex biochemical mechanisms. This raises an important consideration when ligands are designed to explain some of the unpredictable outcomes observed in therapeutic discovery targeting LTA4H. Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation.,Lee KH, Ali NF, Lee SH, Zhang Z, Burdick M, Beaulac ZJ, Petruncio G, Li L, Xiang J, Chung EM, Foreman KW, Noble SM, Shim YM, Paige M Sci Rep. 2022 Jun 8;12(1):9443. doi: 10.1038/s41598-022-13238-6. PMID:35676292 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Leukotriene A4 Hydrolase

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