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Molecular Mechanism of S1P Binding and Activation of the S1P1 Receptor
journal contribution
posted on 2019-10-15, 19:15 authored by Zhenyan Jiang, Hansi ZhangSphingosine-1-phosphate
(S1P) is a lipidic mediator in mammals
that functions either as a second messenger or as a ligand. In the
latter case, it is transported by its HDL-associated apoM carrier
and circulated in blood where it binds to specific S1P receptors on
cell membranes and induces downstream reactions. Although S1P signaling
pathways are essential for many biological processes, they are poorly
understood at the molecular level. Here, the solved crystal structures
of the S1P1 receptor were used to evaluate molecular dynamics
(MD) simulations to generate greater detailed molecular insights into
the mechanism of S1P signaling. The MD simulations provided observations
at the coarse-grained and atomic levels indicating that S1P may access
the receptor binding pocket directly from solvents. Lifting of the
bulky N-terminal cap region of the receptor precedes initial S1P binding.
Glu1213.29 guides S1P penetration, and together with Arg2927.34 is responsible for the stabilization of S1P in the binding
pocket, which is consistent with experimental predictions. The complete
binding of S1P is followed by receptor activation, wherein Trp2696.48 moves toward the transmembrane helix (TM) 7, resulting
in the formation of an enhanced hydrogen bond network in the lower
region of TM7. The distance between TM3 and TM6 is subsequently increased,
resulting in the opening of the intracellular binding pocket that
enables G protein binding. Further analysis of the force distribution
network in the receptor yielded a detailed molecular understanding
of the signal transmission network that is activated upon agonist
binding.
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S 1P BindingTrp 269 6.48 movesG protein bindingS 1P bindinghydrogen bond networksignal transmission networkMDS 1P 1 Receptor Sphingosine -1-phosphateintracellular binding pocketS 1P 1 receptorArg 292 7.34N-terminal cap regionS 1P receptorsTMHDL-associated apoM carrierforce distribution networkGlu 121 3.29 guides S 1P penetrationreceptor binding pocketS 1P
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