Axel Brunger received his Physics Diploma at the University of Hamburg in 1980, and his Ph.D. degree from the Technical University of Munich in 1982 working with Klaus Schulten. He held a NATO postdoctoral fellowship and subsequently became a research associate with Martin Karplus at the Department of Chemistry, Harvard University. In 1987 he joined the faculty in the Department of Molecular Biophysics and Biochemistry at Yale University. In 2000, he moved to Stanford University where he is Professor and Chair of the Department of Molecular and Cellular Physiology. He also holds an appointment as Investigator in the Howard Hughes Medical Institute. In 1995 he was awarded the Rntgen Prize for Biosciences from the University of Wrzburg. In 2003, he received the Gregori Aminoff Award of the Royal Swedish Academy. In 2005 he was elected member of the National Academy of Sciences. In 2011 he received the DeLano Award of the American Society for Biochemistry and Molecular Biology, in 2014 he received the Bernard Katz Award of the Biophysical Society, and the Carl Hermann Medal of the German Crystallographic Society, and in 2016 he received the Trueblood Award of the American Crystallographic Association.
Early in his career, Brunger began developing tools for interpreting x-ray crystallography diffraction data. Scientists use x-ray crystallography to determine molecular structures by crystallizing the molecules and then bombarding them with x-rays. From the data produced by the diffracted x-rays, scientists can calculate a three-dimensional model of the molecule. BrungerŐs powerful computational methodology revolutionized structural calculation, accelerating its automation and making protein crystallography accessible to non-experts.
Brunger broke new ground by developing algorithms to refine crystal structures based on simulated annealing. His techniques helped identify the most accurate and lowest energy structure from x-ray crystallography diffraction data. Simulated annealing allowed scientists to determine certain structures that before were considered intractable or required new diffraction data. He and his colleagues incorporated these algorithms into the computer program X-PLOR, as well as its successor, CNS. Their article describing CNS has been cited more than 18,000 times.
Brunger also developed a major computational tool called the Ňfree R value,Ó to rate a molecular modelŐs quality and how likely it is to be correct. The free R value has since become a standard criterion for judging agreement between a crystallographic model and its experimental x-ray diffraction data.
Since the mid-1990s, Brunger has applied his expertise in structural biology to study the molecular mechanisms of synaptic proteins that enable nerve cell communication. At the time, scientists knew that the SNARE protein complex involved in neurotransmission consists of synaptobrevin, syntaxin-1, and SNAP-25. Synaptic vesicles carry synaptobrevin, along with neurotransmitters, to the nerve cell membraneŐs inner face, which contains syntaxin and SNAP-25. As the respective SNAREs zip up, they fuse the synaptic vesicle membrane and the nerve cell membrane, releasing neurotransmitter from the pre-synaptic neuron.
Brunger and his team showed that the corkscrew-shaped SNARE proteins assemble into quartets of one syntaxin-1, one synaptobrevin, and two SNAP-25 helices. The proteins all lie in parallel, with their heads pointing in the same direction, to promote membrane fusion. Since moving to Stanford in 2000, Brunger and his collaborators have also developed a reconstituted system that enables them to study synaptic fusion at greater level of detail than possible in neurons.
Recently, BrungerŐs team used electron cryo-microscopy to determine the structure of the 20S super-complex: SNARE complex bound to α-SNAP and NSF proteins. This sub-nanometer resolution structure, along with functional studies, revealed new insights into the molecular mechanism of NSF-mediated SNARE complex disassembly, which allows SNARE to be recycled for the next round of synaptic vesicle fusion. The team also determined atomic-resolution structures of the calcium sensor synaptotagmin-1 with the SNARE complex, revealing a conserved interface essential for fast synchronous release of neurotransmitters.