Structure and inhibition of mouse leukotriene C4 synthase.

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)

Publications 9.5.0