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Sodium binding to hH3R and hH4R — a molecular modeling study

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Abstract

Several aminergic GPCRs, e.g., the human histamine H3-receptor (hH3R) are sensitive to sodium ions. Based on these experimental results, including site directed mutagenesis studies, a sodium binding pocket near to the highly conserved Asp2.50 was suggested. Recently, in the crystallized adenosine A2A receptor (4EIY), a sodium ion was found in a pocket, coordinated by Asp52, Ser91, and three water molecules. Despite high homology in amino acid sequence between hH3R and hH4R, pharmacological studies revealed that the hH4R is — in contrast to hH3R — not sensitive to sodium ions. In order to obtain a deeper insight onto the differences in sodium sensitivity between hH3R and hH4R, we performed molecular modelling studies, including molecular dynamic simulations and calculation of Gibbs energy of solvation. The results of the modeling studies suggested that the amino acid at position 7.42 influences sodium binding to aminergic GPCRs in different ways. A comparison of the amino acids forming the sodium binding channel between the ligand binding pocket and the sodium binding pocket of all human aminergic GPCRs showed an 80 % occurrence of glycine — in contrast to hH3R and hH4R. The Gln7.42 at hH4R disrupts a water chain, connecting the Asp3.32 of the orthosteric binding site and the Asp2.50 of the allosteric binding site. Besides, the oxygen of the glutamine side chain stabilizes the interaction of the sodium ion with the Asp3.32. Thus, the binding of the sodium into the allosteric binding site might be hindered kinetically.

Binding of Na+ to hH3R

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Acknowledgments

This work was supported by DFG (STR 1125/1-1) of the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstraße 31, 93040, Regensburg, Germany

    Hans-Joachim Wittmann

  2. Medical School of Hannover, Institute of Pharmacology, Carl-Neuberg-Straße 1, 30625, Hannover, Germany

    Roland Seifert

  3. Department of Pharmaceutical and Medicinal Chemistry II, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstraße 31, 93040, Regensburg, Germany

    Andrea Strasser

Authors
  1. Hans-Joachim Wittmann
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  2. Roland Seifert
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  3. Andrea Strasser
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Correspondence to Andrea Strasser.

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Fig. S1

Alignment of the amino acid sequences of the hA2AR, hβ2R, hH3R, and hH4R. Gray shaded: highly conserved amino acid within each TM domain; yellow shaded: highly conserved cysteine, forming a disulfide bond between the E2-loop and the upper part of TM III; red: amino acids, different between hH3R and hH4R and suggested to be responsible for the observed subtype differences in sodium sensitivity, based on molecular modeling studies. (GIF 75 kb)

High resolution image (TIFF 1644 kb)

Fig. S2

Relative density profile of water and the lipid bilayer. The relative density profile of water and the nitrogens of the POPC lipid bilayer is given as mean value with respect to time for the productive simulation phase of the hH3R. The relative density is calculated independently for the water and the POPC-nitrogen in such a manner that the maximum for both curves is 1. The gray line behind the curve for water indicates the relative water density at 100 different time frames within the productive simulation. (GIF 222 kb)

High resolution image (TIFF 5962 kb)

Fig. S3

Schematic presentation of the lattice used for calculation of the Coulomb potential and Coulomb- and Lennard-Jones interaction surface. Every 10th lattice point is shown as a black dot. Only one exemplary lattice is shown along the y-axis. (GIF 197 kb)

High resolution image (TIFF 2868 kb)

Fig. S4

Hydration numbers for the sodium ion during the binding to hH3R and hH4R. The mean number of oxygens (from water or protein) within a distance less than 0.25 nm, calculated according to “Materials and methods” for distinct penetration states of the sodium ion to hH3R or hH4R. (GIF 76 kb)

High resolution image (TIFF 2047 kb)

Fig. S5

Snapshots of MD simulations regarding the hydration of the sodium ion. The change of the hydration environment of the Na+ is shown exemplary for the orthosteric binding site near Asp3.32 of hH4R. a, the sodium ion is coordinated by the two carboxylic oxygens of Asp3.32 and three water molecules. b, schematic presentation of the rotation of a Na+-H2O unit during the further binding process. c, the sodium ion is hydrated by five water molecules. (GIF 147 kb)

High resolution image (TIFF 4438 kb)

Fig. S6

Alignment of the amino acids, forming the sodium binding channel of the human A2A receptor, mouse μ-opioid receptor and all human aminergic GPCRs. All amino acids, forming the sodium binding channel, are presented within green or yellow boxes. Green: the most conserved amino acid at that position; yellow: amino acids, which are different to the most conserved amino acid at that position. (GIF 242 kb)

High resolution image (TIFF 2124 kb)

Fig. S7

Direct view from Asp3.32 into the sodium channel based on molecular dynamic simulations of hH3R, hH4R-Gln7.42Leu, hH4R-Gln7.42Gly, and hH4R. Shown are snapshots by molecular dynamic simulations. (GIF 192 kb)

High resolution image (TIFF 6020 kb)

Fig. S8

Influence of Val3.40 in hH4R and Ala3.40 in an hH4R-Val3.40Ala mutant onto the sodium binding pocket. Shown are snapshots obtained by molecular dynamic simulations. (GIF 97 kb)

High resolution image (TIFF 2713 kb)

Fig. S9

Influence of the conformation of the Gln7.42 side chain in hH4R onto electrostatic potential in hH4R. a, There is no sodium in the allosteric binding site. b, A sodium ion is present in the allosteric binding site. Shown are snapshots obtained by molecular dynamic simulation. A negative potential is indicated by blue, a more positive potential is indicated by red. (GIF 71 kb)

High resolution image (TIFF 3482 kb)

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Wittmann, HJ., Seifert, R. & Strasser, A. Sodium binding to hH3R and hH4R — a molecular modeling study. J Mol Model 20, 2394 (2014). https://doi.org/10.1007/s00894-014-2394-2

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