Molecular basis of ligand selectivity for melatonin receptors

Abstract

The sandwich structure in human melatonin receptors was disrupted. In MT1 this opened a gate for the water molecule from the bulk environment to fluctuate into the inner space. In MT2, the sandwich structure was stabilized by MEL during the whole MD simulations.

Melatonin receptor structure and signaling

“…The crystal structures of MT 1 and MT 2 receptors were also exploited for the rationalization of structure–activity relationships, in particular for the investigation of the molecular determinants leading to high potency, stereoselectivity, and subtype or functional selectivity. Unbiased molecular dynamics simulations of the N‐anilinoethylamide derivative N‐(2‐((3‐methoxyphenyl)(naphthalen‐2‐yl)amino)ethyl)acetamide ( UCM800 , Figure 1) in complex with MT 1 and MT 2 receptors supported the functional selectivity of the ligand, which was described by the authors as an MT 1 agonist and MT 2 antagonist, 54 even if it has very similar MT 1 and MT 2 intrinsic activities, close to zero 55 . While the MT 2 receptor maintained the crystallized inactive conformation, the different binding arrangement assumed by the ligand at the MT 1 receptor led to a shift of TM1 and TM6 and the formation of a continuous water molecule channel which activates the receptor.…”