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
✍ Scribed by Magdalena J. Ślusarz; Rafał Ślusarz; Jerzy Ciarkowski
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 2006
- Tongue
- English
- Weight
- 540 KB
- Volume
- 81
- Category
- Article
- ISSN
- 0006-3525
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✦ Synopsis
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‐NH~2~, 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~α~ C‐terminal peptide of transducin MII–Gt~α~ (338–350) prototype (Ślusarz, 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. © 2005 Wiley Periodicals, Inc. Biopolymers 81: 321–338, 2006
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