The 3D Structure of Human DP Prostaglandin G-Protein-Coupled Receptor
Bound to Cyclopentanoindole Antagonist, Predicted Using the DuplexBiHelix
Modification of the GEnSeMBLE Method
Version 2 2018-02-20, 20:20
Version 1 2018-02-20, 20:17
Posted on 2018-02-20 - 20:20
Prostaglandins play a critical physiological
role in both cardiovascular and immune systems, acting through their
interactions with 9 prostanoid G protein-coupled receptors (GPCRs).
These receptors are important therapeutic targets for a variety of
diseases including arthritis, allergies, type 2 diabetes, and cancer.
The DP prostaglandin receptor is of interest because it has unique
structural and physiological properties. Most notably, DP does not
have the 3–6 ionic lock common to Class A GPCRs. However, the
lack of X-ray structures for any of the 9 prostaglandin GPCRs hampers
the application of structure-based drug design methods to develop
more selective and active medications to specific receptors. We predict
here 3D structures for the DP prostaglandin GPCR, based on the GEnSeMBLE
complete sampling with hierarchical scoring (CS-HS) methodology. This
involves evaluating the energy of 13 trillion packings to finally
select the best 20 that are stable enough to be relevant for binding
to antagonists, agonists, and modulators. To validate the predicted
structures, we predict the binding site for the Merck cyclopentanoindole
(CPI) selective antagonist docked to DP. We find that the CPI binds
vertically in the 1–2–7 binding pocket, interacting
favorably with residues R3107.40 and K762.54 with additional interactions with S3137.43, S3167.46, S191.35, etc. This binding site differs significantly
from that of antagonists to known Class A GPCRs where the ligand binds
in the 3–4–5–6 region. We find that the predicted
binding site leads to reasonable agreement with experimental Structure–Activity
Relationship (SAR). We suggest additional mutation experiments including
K762.54, E1293.49, L1233.43, M2706.40, F2746.44 to further validate the structure,
function, and activation mechanism of receptors in the prostaglandin
family. Our structures and binding sites are largely consistent and
improve upon the predictions by Li et al. (J. Am. Chem. Soc. 2007, 129 (35), 10720) that used our earlier MembStruk prediction methodology.
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Shankar, Vishnu; Goddard, William A.; Kim, Soo-Kyung; Abrol, Ravinder; Liu, Fan (2018). The 3D Structure of Human DP Prostaglandin G-Protein-Coupled Receptor
Bound to Cyclopentanoindole Antagonist, Predicted Using the DuplexBiHelix
Modification of the GEnSeMBLE Method. ACS Publications. Collection. https://doi.org/10.1021/acs.jctc.7b00842
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AUTHORS (5)
VS
Vishnu Shankar
WG
William A. Goddard
SK
Soo-Kyung Kim
RA
Ravinder Abrol
FL
Fan Liu
KEYWORDS
3 D structuresCPIDP prostaglandin GPCRS 19 1.359 prostanoid G protein-coupled receptorsS 316 7.46SAR9 prostaglandin GPCRsstructure-based drug design methodsantagonistF 274 6.44L 123 3.43MembStruk prediction methodologyDP prostaglandin receptorCS-HS3 D StructureHuman DP Prostaglandin G-Protein-Coupled Receptor BoundM 270 6.40type 2 diabetesbinding siteE 129 3.49K 76 2.54residues R 310 7.40GEnSeMBLE Method ProstaglandinsS 313 7.43