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 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, and in 2014, he received both the Bernard Katz Award of the Biophysical Society and the Carl Hermann Medal of the German Crystallographic Society. 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 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 “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. At the time, scientists knew that the SNARE protein complex involved in neurotransmission consisted of synaptobrevin, syntaxin-1, and SNAP-25. Synaptic vesicles carry synaptobrevin, along with neurotransmitters, to the nerve cell membrane’s 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.
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 live 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 and 2018, 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 2015 and 2017, Brunger’s 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.