A Usual G‐Protein‐Coupled Receptor in Unusual Membranes

G‐protein‐coupled receptors (GPCRs) are the largest family of membrane‐bound receptors and constitute about 50 % of all known drug targets. They offer great potential for membrane protein nanotechnologies. We report here a charge‐interaction‐directed reconstitution mechanism that induces spontaneous insertion of bovine rhodopsin, the eukaryotic GPCR, into both lipid‐ and polymer‐based artificial membranes. We reveal a new allosteric mode of rhodopsin activation incurred by the non‐biological membranes: the cationic membrane drives a transition from the inactive MI to the activated MII state in the absence of high [H⁺] or negative spontaneous curvature. We attribute this activation to the attractive charge interaction between the membrane surface and the deprotonated Glu134 residue of the rhodopsin‐conserved ERY sequence motif that helps break the cytoplasmic “ionic lock”. This study unveils a novel design concept of non‐biological membranes to reconstitute and harness GPCR functions in synthetic systems.     

The Dawn of X‐Ray Astronomy (Nobel Lecture)

Riccardo Giacconi joined the American Science and Engineering Corporation (AS & E) after leaving Princeton University in 1959, and in 1962 his group there detected the first extrasolar Xray source. Prof. Giacconi was subsequently responsible for the launch and use of the satellite UHURU (1970) and the EINSTEIN observatory (1978). He was appointed Associate Director of the High Energy Astrophysics Division of the Harvard‐Smithsonian Center for Astrophysics in 1973 and was also appointed Professor of Astronomy at Harvard University that same year. In 1981 he became the first Director of the Space Telescope Science Institute and was also appointed Professor in the Department of Physics and Astronomy at Johns Hopkins University. In 1992 he was appointed Director General of the European Southern Observatory, an intergovernmental organization of eight nations. Prof. Giaconni is currently President of Associated Universities, Inc., and Research Professor at Johns Hopkins University. He was awarded the Wolf Prize in 1987, and the Nobel Prize for Physics in 2002.     

A Half‐Century with Solar Neutrinos (Nobel Lecture)

The Sun derives its energy from fusion reactions in which hydrogen is transformed into helium. Every time four protons are turned into a helium nucleus, two neutrinos are produced. These neutrinos take only two seconds to reach the surface of the Sun and another eight minutes or so to reach the Earth. Thus, neutrinos tell us what happened in the center of the Sun eight minutes ago. The Sun produces one‐third as many neutrinos as predicted by the standard solar model of particle physics. The author's pioneering work proved that nothing was wrong with the experiments or the theory; something was “wrong” with the neutrinos, in the sense that they behave in ways beyond the standard model.     

Allosteric Optical Control of a Class B G‐Protein‐Coupled Receptor

Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G‐protein‐coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light‐activated positive allosteric modulator of the glucagon‐like peptide‐1 receptor (GLP‐1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans. PhotoETP potentiates Ca²⁺, cAMP, and insulin responses to glucagon‐like peptide‐1 and its metabolites following illumination of cells with blue light. PhotoETP thus provides a blueprint for the production of small‐molecule class B GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP‐1R.     

The Identification of the Sodium–Potassium Pump (Nobel Lecture)

Deemed too provocative , the word “pump” was omitted in the title of the 1957 publication “The Influence of Some Cations on an Adenosine Triphosphatase from Peripheral Nerves”, in which J. C. Skou showed that an ATPase in the membrane of crab nerves had such characteristics from the point of view of substrate ATP and effect of Na and K that it was reasonable to suggest that it was involved in the active transport of Na across the cell membrane.     

A Structural Basis of Light Energy and Electron Transfer in Biology (Nobel Lecture)

Aspects of intramolecular light energy and electron transfer are discussed for three protein cofactor complexes whose three-dimensional structures have been elucidated by X-ray crystallography: the light harvesting phycobilisomes of cyanobacteria, the reaction center of purple bacteria, and the blue multi-copper oxidases. A wealth of functional data is available for these systems which allows specific correlations to be made between structure and function and general conclusions to be drawn about light energy and electron transfer in biological materials.