133
Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II
80-POS
Board 33
The Last 10 Residues of Human Sphingosine-1-Phosphate Receptor 1 Interacts with G-
Protein Coupled Receptor Kinases in A Conserved Manner
Emel Sen
1
, Yusuf Dogus Dogru
1
, Ozlem Keskin
1
, Attila Gursoy
1
, Kumlesh K. Dev
2
.
1
Koc University, Istanbul, Turkey,
2
Trinity College Dublin, Dublin, Ireland.
Sphingosine-1-phosphate receptors are a family of G-protein coupled receptors (GPCRs) highly
expressed in human cells. They have roles in cellular proliferation, survival and migration.
Similar to other GPCRs, Sphingosine-1-phosphate receptor 1 (S1PR1) C-terminal internalization
via phosphorylation is an important intracellular mechanism for the downstream signaling. To
better understand S1PR1 pathways, we synthesized a peptide consisting of the last 10 residues of
the C-terminal of S1PR1, which we termed MNP301. We experimentally showed that MNP301
prevents S1PR1 internalization and uncouples the agonistic effect of phosphorylated FTY720, a
modulator of S1PR1. However, how these last 10 residues prevent S1PR1 redistribution is still
unclear. Several studies show that G-protein coupled receptor kinases (GRKs) are involved in the
S1PR1 internalization and C-terminal phosphorylation. In this study, we investigated the specific
interactions of these last 10 residues and GRKs by using three different docking tools. Our
analysis shows that all GRKs available in Protein Data Bank (GRK1, GRK2, GRK3 and GRK6)
bind to MNP301 from the same binding pocket with similar energy values. Our in silico results
suggest that the peptide binds to GRKs in between their N-terminal regulator of G-protein
signaling (RGS) domain and protein kinase domain. We will further use Molecular Dynamics
(MD) and Perturbation Response Scanning (PRS) tools to give insight into the binding
mechanism and allosteric residues of GRKs. A deeper comprehension of these interactions will
contribute a better understanding of S1PR1 signaling pathways.
