Residues from Transmembrane Helices 3 and 5 Participate in Leukotriene B4 Binding to BLT1

Leukotrienes are inflammatory mediators that bind to seven transmembrane, G-protein-coupled receptors (GPCRs). Here we examine residues from transmembrane helices 3 and 5 of the leukotriene B4 (LTB4) receptor BLT1 to elucidate how these residues are involved in ligand binding. We have selected these...

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Bibliographic Details
Published inBiochemistry (Easton) Vol. 45; no. 18; pp. 5733 - 5744
Main Authors Sabirsh, Alan, Bywater, Robert P, Bristulf, Jesper, Owman, Christer, Haeggström, Jesper Z
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 09.05.2006
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Summary:Leukotrienes are inflammatory mediators that bind to seven transmembrane, G-protein-coupled receptors (GPCRs). Here we examine residues from transmembrane helices 3 and 5 of the leukotriene B4 (LTB4) receptor BLT1 to elucidate how these residues are involved in ligand binding. We have selected these residues on the basis of (1) amino acid sequence analysis, (2) receptor binding and activation studies with a variety of leukotriene-like ligands and recombinant BLT1 receptors, (3) previously published recombinant BLT1 mutants, and (4) a computed model of the active structure of the BLT1 receptor. We propose that LTB4 binds with the polar carboxylate group of LTB4 near the extracellular surface of BLT1 and with the hydrophobic LTB4 tail pointing into the transmembrane regions of the receptor protein. The carboxylate group and the two hydroxyls of LTB4 interact with Arg178 and Glu185 in transmembrane helix 5. Residues from transmembrane helix 3, Val105 and Ile108, also line the pocket deeper inside the receptor. LTB4 is becoming increasingly important as an immunomodulator during a number of pathologies, including atherosclerosis. Detailed information about the LTB4 binding mechanism, and the receptor residues involved, will hopefully aid in the design of new immunomodulatory drugs.
Bibliography:ark:/67375/TPS-9D03P8P1-S
istex:70E9EA6D545C23726FED1D1A4660FEF9BA25A142
This study was financially supported by the AFA Health Foundation, the Swedish Medical Research Council (03X-10350), Konung Gustav V:s 80 årsfond, and EC FP6 funding (LSHM-CT-2004-005033). This publication reflects only the author's views. The European Commission is not liable for any use that may be made of information herein.
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ISSN:0006-2960
1520-4995
DOI:10.1021/bi060076t