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Computational analysis of ligand recognition mechanisms by prostaglandin E2 (subtype 2) and D2 receptors

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Abstract

The eight members of the prostanoid receptor family belong to the class A G protein-coupled receptors. We investigated the evolutionary relationship of the eight members by a molecular phylogenetic analysis and found that prostaglandin E2 receptor subtype 2 (EP2) and prostaglandin D2 receptor (DP) were closely related. The structures of the ligands for the two receptors are similar to each other but are distinguished by the exchanged locations of the carbonyl oxygen and the hydroxy group in the cyclopentane ring. The ligand recognition mechanisms of the receptors were examined by an integrated approach using several computational methods, such as amino acid sequence comparison, homology modeling, docking simulation, and molecular dynamics simulation. The results revealed the similar location of the ligand between the two receptors. The common carboxy group of the ligands interacts with the Arg residue on the seventh transmembrane (TM) helix, which is invariant among the prostanoid receptors. EP2 uses a Ser on TM1 to recognize the carbonyl oxygen in the cyclopentane ring of the ligand. The Ser is specifically conserved within EP2. On the other hand, DP uses a Lys on TM2 to recognize the hydroxy group of the ω chain of the ligand. The Lys is also specifically conserved within DP. The interaction network between the D(E)RY motif and TM6 was found in EP2. However, DP lacked this network, due to the mutation in the D(E)RY motif. Based on these observations and the previously published mutational studies on the motif, the possibility of another activation mechanism that does not involve the interaction between the D(E)RY motif and TM6 will be discussed.

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Acknowledgments

We thank Drs. Wataru Nemoto, Kentaro Tomii, and Makiko Suwa of CBRC for useful discussions on this work. HD was supported in part by the Global COE program, “an In Silico Medicine”, at Osaka University and Grants-in-Aid (Nos. 20650012 and 19650072) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. HT was partially supported by Targeted Proteins Research Program (TPRP).

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Authors and Affiliations

  1. The Center for Medical Engineering and Informatics, Osaka University, 1-5, Yamadaoka, Suita Osaka, 565-0871, Japan

    Hiromi Daiyasu

  2. Computational Biology Research Center, Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan

    Takatsugu Hirokawa & Hiroyuki Toh

  3. Institute for Protein Research, Osaka University, 6-2-3, Furuedai, Suita Osaka, 565-0874, Japan

    Narutoshi Kamiya

  4. Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Hiroyuki Toh

Authors
  1. Hiromi Daiyasu
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  2. Takatsugu Hirokawa
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  3. Narutoshi Kamiya
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  4. Hiroyuki Toh
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Corresponding author

Correspondence to Hiromi Daiyasu.

Additional information

Dedicated to Professor Akira Imamura on the occasion of his 77th birthday and published as part of the Imamura Festschrift Issue.

Electronic supplementary material

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Supplement 1 Database search results (EPS 209 kb)

214_2011_1034_MOESM2_ESM.eps

Supplement 2 Multiple alignment of prostanoid receptor homologues. The alignment was used to construct the phylogenetic tree shown in Fig. 2. The gi number for each sequence is shown on the left side of the alignment. The information about the source organism and the receptor name are provided in Fig. 2. The D(E)RY motif and the NPxxY motif are indicated by blue rectangles. The second residue in the D(E)RY motif of DP is colored pink (EPS 1,637 kb)

Supplement 3 Validation of model structures (EPS 994 kb)

Supplement 4 Docking results (EPS 218 kb)

Supplement 5 Cα RMSD for the EP2 and DP models (EPS 947 kb)

Supplement 6 Potential energies for the EP2 and DP models (EPS 692 kb)

214_2011_1034_MOESM7_ESM.eps

Supplement 7 Time series of the distances between the atom pairs involved in the formation of the intramolecular networks for the EP2 and DP models (EPS 9,880 kb)

Supplement 8 Cα RMSF for the EP2 and DP models (EPS 2,315 kb)

Supplement 9 Interaction energies of the ligand-receptor complexes for the EP2 and DP models (EPS 210 kb)

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Daiyasu, H., Hirokawa, T., Kamiya, N. et al. Computational analysis of ligand recognition mechanisms by prostaglandin E2 (subtype 2) and D2 receptors. Theor Chem Acc 130, 1131–1143 (2011). https://doi.org/10.1007/s00214-011-1034-5

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