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 Röntgen Prize for Biosciences from the University of Würzburg. 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. In 2021 he was elected member of the American Academy of Arts & Sciences.
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. Brunger’s powerful computational methodology revolutionized structural calculation, accelerating its automation and making protein crystallography accessible to non-experts.
Brunger also developed a major computational tool called the “free R value,” to rate a molecular model’s 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.
In 1998, 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 University in 2000, Brunger and his collaborators have developed a reconstituted system that enables them to study synaptic fusion at greater level of detail than possible in neurons. The team studied the molecular mechanism of neuronal SNAREs, complexin, and synaptotagmin, as well as other factors involved in priming and pre-synaptic plasticity.
In 2015, Brunger’s team used electron cryo-microscopy to determine the structure of the supercomplex of SNAREs, the ATPase NSF, and the adapter protein α-SNAP. This subnanometer-resolution structure, along with functional studies, revealed first glimpses of the molecular mechanism of NSF-mediated SNARE complex disassembly, which allows SNARE to be recycled for the next round of synaptic vesicle fusion.
In 2017, the team determined atomic-resolution structures of the complex of the calcium sensor synaptotagmin-1, the regulator complexin, and the SNARE complex, revealing two essential interfaces that are essential for fast synchronous release of neurotransmitters. . These structures suggest an unlocking mechanism that is triggered by Ca2+binding to the synaptotagmin molecules, leading to SNARE complex zippering, and membrane fusion.