Investigation of mechanism of desmopressin binding in vasopressin V2 receptor versus vasopressin V1a and oxytocin receptors: Molecular dynamics simulation of the agonist‐bound state in the membrane–aqueous system

Abstract

The vasopressin V2 receptor (V2R) belongs to the Class A G protein-coupled receptors (GPCRs). V2R is expressed in the renal collecting duct (CD), where it mediates the antidiuretic action of the neurohypophyseal hormone arginine vasopressin (CYFQNCPRG-NH2, AVP). Desmopressin ([1-deamino, 8-D]AVP, dDAVP) is strong selective V2R agonist with negligible pressor and uterotonic activity. In this paper, the interactions responsible for binding of dDAVP to vasopressin V2 receptor versus vasopressin V1a and oxytocin receptors has been examined. Three-dimensional activated models of the receptors were constructed using the multiple sequence alignment and the complex of activated rhodopsin with Gt(alpha) C-terminal peptide of transducin MII-Gt(alpha) (338-350) prototype (Slusarz, R.; Ciarkowski, J. Acta Biochim Pol 2004 51, 129-136) as a template. The 1-ns unconstrained molecular dynamics (MD) of receptor-dDAVP complexes immersed in the fully hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) membrane model was conducted in an Amber 7.0 force field. Highly conserved transmembrane residues have been proposed as being responsible for V2R activation and G protein coupling. Molecular mechanism of the dDAVP binding has been suggested. The internal water molecules involved in an intricate network of the hydrogen bonds inside the receptor cavity have been identified and their role in the stabilization of the agonist-bound state proposed.

Molecular Modeling of Vasopressin V2 Receptor Tetramer in Hydrated Lipid Membrane

“…At the beginning of building the model we have used the initial model of activated V2R, so we were able to observe its characteristic conformational changes during MD simulation. Accordingly, we have verified previously proposed V2R amino acid residues responsible for vasopressin and Gsa (Ile 382 -Leu 394 ) binding [122,120,121] and we have found that they are mutually consistent. The analyzed deviations of 7TM observed during unconstrained MD simulation and presented as the RMSd evolution accompanying the MD progress are also consistent with previous assumptions.…”

“…We have only used them as a biased criterion of accuracy of changes during MD simulation. The retention of previously reported interactions [120,121] has let us confirm as to current MD condition being correct. All currently identified interactions agree with those found previously, and reported by Ś lusarz et al [121] (see Table 3).…”

“…Additionally, we have inspected residues involved in V2R* -AVP and V2R -Gsa(Ile 382 -Leu 394 ) interactions. Because of the shortage of experimental data considering these interactions we have validated our with reference to the computational data of Ś lusarz et al [120,121]. The obtained V2R* -AVP and V2R* -Gsa (Ile 382 -Leu 394 ) interactions were previously compared with available experimental data [121].…”

A case of nephrogenic diabetes insipidus with a novel missense mutation in the AVPR2 gene

“…compbio.ucsf.edu/, entry name o43192 _ HUMAN; University of California San Francisco, San Francisco, CA, USA). Moreover, the TM structure of our model appeared to be similar to Susarz's model [26], considering the positional relationship of each residue.…”

An Influence of the Aromatic Side Chains Conformations in Positions 2 and 3 of Vasopressin Analogs on Interactions with Vasopressin and Oxytocin Receptors

“…The equivalent arginyl (R46 and R34 in V 1a R and OTR, respectively) has been identified as playing a critical role in high affinity agonist binding [45,46]. Moreover, the molecular basis for the significance of this residue for dDAVP binding in V 2 R has been proposed in our earlier paper [38]. Other crucial residue which appears in V 2 R is the nonconserved D103 located in the first extracellular loop.…”