Dynamic Structural Investigations on the Torpedo Nicotinic Acetylcholine Receptor by Time-Resolved Photoaffinity Labeling

• Published in: Chembiochem : a European journal of chemical biology Vol. 7; no. 4; pp. 570 - 583
• Main Authors: Mourot, Alexandre, Grutter, Thomas, Goeldner, Maurice, Kotzyba-Hibert, Florence
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 03.04.2006; WILEY-VCH Verlag; WILEY‐VCH Verlag
• Subjects: Animals; bioorganic chemistry; Chemical Sciences; conformation analysis; membrane proteins; Molecular Structure; nicotinic acetylcholine receptor; Other; Photoaffinity Labels - chemistry; Photoaffinity Labels - pharmacology; Protein Conformation; Protein Structure, Tertiary; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - drug effects; Receptors, Nicotinic - physiology; site-directed labeling; Structure-Activity Relationship; Time Factors; Torpedo
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.200500526

An increasing number of high-resolution structures of membrane-embedded ion channels (or soluble homologues) have emerged during the last couple of years. The most pressing need now is to understand the complex mechanism underlying ion-channel function. Time-resolved photoaffinity labeling is a suitable tool for investigating the molecular function of membrane proteins, especially when high-resolution structures of related proteins are available. However until now this methodology has only been used on the Torpedo nicotinic acetylcholine receptor (nAChR). nAChRs are allosteric cation-selective receptor channels that are activated by the neurotransmitter acetylcholine (ACh) and implicated in numerous physiological and pathological processes. Time-resolved photoaffinity labeling has already enabled local motions of nAChR subdomains (i.e. agonist binding sites, ion channel, subunit interface) to be understood at the molecular level, and has helped to explain how small molecules can exert their physiological effect, an important step toward the development of drug design. Recent analytical and technical improvements should allow the application of this powerful methodology to other membrane proteins in the near future.