Structure of a GPCR target for multiple sclerosis treatment
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Figure: Crystal structure of the
human lipid GPCR. The S1P1 receptor reveals a highly organized
N-terminus that limits access of the lysophospholipid ligand
sphingosine-1-phosphate to the binding pocket from the extracellular
environment. The zwitterionic ligand (shown in green, red and blue) is
postulated to insert in the plasma membrane and then diffuse into the
receptor pocket through a tunnel deep within the lipid bilayer that is
bounded by transmembrane domains I and VII. The background shows the brain
and neurons, a key target for S1P1 agonists in the treatment of
multiple sclerosis. (courtesy of TSRI). |
Ray Stevens group (The Scripps Research Institute) and collaborators
The Stevens group solved the structure of a G
protein-coupled receptor (GPCR) involved in the treatment of multiple
sclerosis. Lyso-phospholipid sphingosine-1-phosphate modulates lymphocyte
trafficking, endothelial development and integrity, heart rate, and vascular
tone and maturation by activating the sphingosine-1-phosphate receptor 1
(S1P1), a receptor belonging to a subclass of the GPCR family
originally termed the endothelial differentiation gene (EDG) family of lipid
receptors. Activation of the S1P1 receptor through exogenous
ligands, both physiological and pharmacological, results in significant
inhibition of lymphocyte re-circulation. Modulation of S1P1 is
the basis for the development of the nonselective S1P receptor agonist
prodrug fingolimod (GILENYA(R)), approved in 2010 for the clinical treatment
of relapsing-remitting multiple sclerosis. The structure of S1P1
was determined through a collaboration of scientists from Receptos and the
PSI-sponsored GPCR Network project. The S1P1 structure shows that
extracellular access to the binding pocket is occluded by the amino terminus
and extracellular loops of the receptor. Unlike all other human GPCR
structures solved to date, ligands gain access by entering laterally between
helices I and VII within the transmembrane region of the receptor. The
structure, along with mutagenesis, agonist structure-activity relationship
data, and modeling, provides a detailed view of the molecular recognition and
requirement for hydrophobic volume that activates S1P1, resulting
in the modulation of immune and stromal cell responses.
Citation:
Hanson, MA, Roth, CB, Jo, E, Griffith, MT, Scott, FL, Reinhart, G, Desale, H,
Clemons, B, Cahalan, SM, Schuerer, SC, Sanna, MG, Han, GW, Kuhn, P, Rosen, H,
and Stevens, RC. Crystal structure of a lipid G protein-coupled receptor,
Science 335, 851-855 (2012)
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