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Residues from transmembrane helices 3 and 5 participate in leukotriene B-4 binding to BLT1

Sabirsh, A ; Bywater, RP ; Bristulf, Jesper LU ; Owman, Christer LU and Haeggstrom, JZ (2006) In Biochemistry 45(18). p.5733-5744
Abstract
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 B-4 (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... (More)
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 B-4 (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, Val 105 and Ile 108, 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. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochemistry
volume
45
issue
18
pages
5733 - 5744
publisher
The American Chemical Society (ACS)
external identifiers
  • wos:000237472100006
  • pmid:16669617
  • scopus:33646478846
ISSN
0006-2960
DOI
10.1021/bi060076t
language
English
LU publication?
yes
id
b7b782b1-7572-42ad-817d-48c20b172cb5 (old id 409783)
date added to LUP
2016-04-01 11:44:57
date last changed
2021-06-08 03:58:30
@article{b7b782b1-7572-42ad-817d-48c20b172cb5,
  abstract     = {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 B-4 (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, Val 105 and Ile 108, 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.},
  author       = {Sabirsh, A and Bywater, RP and Bristulf, Jesper and Owman, Christer and Haeggstrom, JZ},
  issn         = {0006-2960},
  language     = {eng},
  number       = {18},
  pages        = {5733--5744},
  publisher    = {The American Chemical Society (ACS)},
  series       = {Biochemistry},
  title        = {Residues from transmembrane helices 3 and 5 participate in leukotriene B-4 binding to BLT1},
  url          = {http://dx.doi.org/10.1021/bi060076t},
  doi          = {10.1021/bi060076t},
  volume       = {45},
  year         = {2006},
}