Dr. Nieng Yan received her B.S. degree from the Department of Biological Sciences & Biotechnology, Tsinghua University, Beijing, China, in 2000. She then pursued her PhD in the Department of Molecular Biology at Princeton University under the supervision of Prof. Yigong Shi between 2000 and 2004. She was the regional winner of the Young Scientist Award (North America) co-sponsored by Science/AAAS and GE Healthcare in 2005 for her thesis on the structural and mechanistic study of programmed cell death. She continued her postdoctoral training at Princeton University, focusing on the structural characterization of intramembrane proteases. In 2007, she joined the faculty of School of Medicine, Tsinghua University. Her lab has been mainly focusing on the structural and functional study of membrane transport proteins exemplified by the glucose transporters and Nav/Cav channels. In 2012 and 2013, she was promoted to tenured professor and Bayer Endowed Chair Professor, respectively. She returned to Princeton University as the founding Shirley M. Tilghman Professor of Molecular Biology in 2017. Dr. Yan was an HHMI international early career scientist in 2012-2017, the recipient of the 2015 Protein Society Young Investigator Award, the 2015 Beverley & Raymond Sackler International Prize in Biophysics, the Alexander M. Cruickshank Award at the GRC on membrane transport proteins in 2016, the 2018 FAOBMB Award for Research Excellence, and the 2019 Weizmann Women & Science Award. She was elected as an International Member of the US National Academy of Sciences in 2019 and an International Honorary Member of the American Academy of Arts and Sciences in 2021.
Voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. Being associated with a variety of disorders, Nav channels are targeted by multiple pharmaceutical drugs and natural toxins. We determined the crystal structure of a bacterial Nav channel NavRh in a potentially inactivated state more than a decade ago. Employing the modern methods of cryo-EM, we determined the near atomic resolution structures of a Nav channel from American cockroach (designated NavPaS) and from electric eel (designated EeNav1.4). Most recently, we have determined the cryo-EM structures of representative human Nav channels (Nav1.1/1.2/1.4/1.5/1.7) in complex with distinct auxiliary subunits, toxins, and drugs.These structures reveal the folding principle and structural details of the single-chain eukaryotic Nav channels that are distinct from homotetrameric voltage-gated ion channels. The structures were captured in drastically different states. Whereas the structure of NavPaS has a closed pore and the four VSDs in distinct conformations, the others are semi-open at the intracelluar gate with VSDs exhibiting similar “up”states. The most striking conformational differenc occurs to the III-IV linker, which is essential for fast inactivation. Based on the structural features, we suggest a “door-wedge” allosteric blocking mechanism for fast inactivation of Nav channels. Structural comparison of the conformationally distinct Nav channels provides important insights into the electromechanical coupling mechanism of Nav channels and offers the 3D template to map hundredes of disease mutations.