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Niegowski D, Kleinschmidt T, Ahmad S, Qureshi AA, Mårback M, Rinaldo-Matthis A, Haeggström JZ
PLoS ONE 9 (5) e96763 [2014-05-08; online 2014-05-08]
Leukotriene (LT) C4 synthase (LTC4S) is an integral membrane protein that catalyzes the conjugation reaction between the fatty acid LTA4 and GSH to form the pro-inflammatory LTC4, an important mediator of asthma. Mouse models of inflammatory disorders such as asthma are key to improve our understanding of pathogenesis and potential therapeutic targets. Here, we solved the crystal structure of mouse LTC4S in complex with GSH and a product analog, S-hexyl-GSH. Furthermore, we synthesized a nM inhibitor and compared its efficiency and binding mode against the purified mouse and human isoenzymes, along with the enzymes' steady-state kinetics. Although structural differences near the active site and along the C-terminal α-helix V suggest that the mouse and human LTC4S may function differently in vivo, our data indicate that mouse LTC4S will be a useful tool in future pharmacological research and drug development.
Chemical Biology Consortium Sweden (CBCS) [Service]
Protein Science Facility (PSF)
PubMed 24810165
DOI 10.1371/journal.pone.0096763
Crossref 10.1371/journal.pone.0096763
pii: PONE-D-14-10371
pmc: PMC4014545
Laboratories for Chemical Biology at Karolinska Institutet (LCBKI)