Holistic approaches to receptor and channel structure and dynamics.

A detailed three-dimensional structure of a molecule is a necessary, but not sufficient prerequisite to understanding its behaviour. Crystal structures are lacking for protein receptors and ion channels. However, the amino acid sequences for representatives of the most important superfamilies of neuroactive proteins (ligand-gated ion channels, voltage-gated ion channels and G-protein receptors) are known. To address the problem of three-dimensional structure and, subsequently, the dynamic properties of these molecules, a holistic approach was applied to the nicotinic acetylcholine receptor (nAChR), the sodium channel of nerves (NaC) and rhodopsin (Rh) to build 'working' structures. For nAChR and Rh, the chains are placed within an envelope derived from image analysis of electron micrographs. Physical organic principles suggest how to juxtapose binding groups as well as structures for ion channels, leading to the identification of the most common feature of channels, the positively charged 'S4' segment and the ever-present amphiphilic segment of nAChR proteins, which has homologous counterparts in the glutamate receptor and glutamate-binding proteins. The cyclic GMP-gated NaC (cGMP-NaC) is related to the eel and rat neuronal NaC, and has a novel positively charged control sequence.