高寧

2017/4-至今，任北京大學生命科學學院教授。

2017/4-至今，任北京大學-清華大學聯合生命中心研究員。

2008/11-2017/3，任清華大學生命科學學院特別副研究員、助理教授、副教授（with tenure），教授。

2006-2008，任紐約州Wadsworth Center，霍華德休斯醫學研究所，哥倫比亞大學生化和分子生物物理系博士后。

運用冷凍電鏡三維重構技術和生物化學及分子生物學手段進行生物大分子複合物的結構與功能研究。現有的工作重點包括原核和真核核糖體體內組裝的機制和調控以及蛋白翻譯的調控機制研究。

科學研究

2016年12月，高寧課題組和合作者在《Nature》（Doi:10.1038/nature20822）發表研究論文，報道了細菌中non-stop mRNA在核糖體上的翻譯終止狀態複合物的高分辨冷凍電鏡結構，並揭示了ArfA在non-stop mRNA翻譯終止過程中的作用機制；他們在體外組裝了ArfA/RF2、non-stop mRNA、tRNA與70S核糖體的複合物，並獲得了該複合物的高分辨冷凍電鏡結構，結構表明ArfA C端的loop結合於核糖體30S小亞基上的mRNA進入通道，並佔據了終止密碼子的部分結合位點，而N端則直接與30S解碼中心及RF2相互作用。進一步分析表明ArfA扮演了兩個重要角色：N端作為mRNA長度的感受器，如果核糖體尚未行進到mRNA的3’末端，mRNA進入通道內的核苷酸會阻礙ArfA的結合；C端則通過和RF2直接結合，從功能上補償了終止密碼子對RF2的激活效應。該研究展示了具有極大結構柔性的小蛋白可以通過結構模擬來取代mRNA上的三鹼基終止密碼子的功能。

學術成果

1.Ma, C., Kurita, D., Li, N., Chen, Y., Himeno, H.#, and Gao, N.# (2017). Mechanistic insights into the alternative translation termination by ArfA and RF2. Nature 541, 550-553.

2.Ma, C., Wu, S., Li, N., Chen, Y., Yan, K., Li, Z., Zheng, L., Lei, J., Woolford, J.L., Jr.#, and Gao, N.# (2017). Structural snapshot of cytoplasmic pre-60S ribosomal particles bound by Nmd3, Lsg1, Tif6 and Reh1. Nat Struct Mol Biol 24, 214-220.

3.Zhai, Y., Cheng, E., Wu, H., Li, N., Yung, P.Y., Gao, N.#, and Tye, B.K.# (2017). Open-ringed structure of the Cdt1-Mcm2-7 complex as a precursor of the MCM double hexamer. Nat Struct Mol Biol 24, 300-308.

4.Li, N., Wu, J.X., Ding, D., Cheng, J., Gao, N.#, and Chen, L.# (2017). Structure of a Pancreatic ATP-Sensitive Potassium Channel. Cell 168, 101-110 e110.

·Recommended by “F1000”

5.Wu, S., Tan, D., Woolford, J.L., Jr., Dong, M.Q., and Gao, N.# (2017). Atomic modeling of the ITS2 ribosome assembly subcomplex from cryo-EM together with mass spectrometry-identified protein-protein crosslinks. Protein Science 26, 103-112.

6.Gu, J., Wu, M., Guo, R., Yan, K., Lei, J., Gao, N.#, and Yang, M.# (2016) Architecture of mammalian respirasome, Nature, 537, 639-643. DOI:10.1038/nature19359

·Recommended by “F1000”

7.Wu, S., Tutuncuoglu, B., Yan, K., Brown, H., Zhang, Y., Tan, D., Gamalinda, M., Yuan, Y., Li, Z., Jakovljevic, J., Ma, C., Lei, J., Dong, M.-Q., Woolford, J.L.#, and Gao, N.# (2016). Diverse roles of assembly factors revealed by structures of late nuclear pre-60S ribosomes. Nature 534, 133-137.

·Recommended by “F1000”, In F1000Prime, 13 Jun 2016; DOI: 10.3410/f.726394793.793519322.

8.Dong, D., Ren, K., Qiu, X., Zheng, J., Guo, M., Guan, X., Liu, H., Li, N., Zhang, B., Yang, D., Ma, C., Wang, S., Wu, D., Ma, Y., Fan, S., Wang, J., Gao, N., and Huang, Z. (2016). The crystal structure of Cpf1 in complex with CRISPR RNA. Nature 532, 522-526.

9.Ma, C., Yan, K., Tan, D., Li, N., Zhang, Y., Yuan, Y., Li, Z., Dong, M.Q., Lei, J., and Gao, N.# (2016). Structural dynamics of the yeast Shwachman-Diamond syndrome protein (Sdo1) on the ribosome and its implication in the 60S subunit maturation. Protein & Cell 7, 187-200.

10.Zhang, D., Yan, K., Liu, G., Song, G., Luo, J., Shi, Y., Cheng, E., Wu, S., Jiang, T., Lou, J., Gao, N. #, and Qin, Y.# (2016). EF4 disengages the peptidyl-tRNA CCA end and facilitates back-translocation on the 70S ribosome. Nat Struct Mol Biol 23, 125-131.

11.Zhang, J., Pan, X., Yan, K, Sun, S., Gao, N.# and Sui, S-F#. (2015). Mechanisms of ribosome stalling by SecM at multiple elongation steps. eLife, DOI: 10.7554/eLife.09684

12.Zhang, Y., Mandava, C.S., Cao, W., Li, X., Zhang, D., Li, N., Zhang, Y., Zhang, X., Qin, Y., Mi, K., Lei, J.#, Sanyal, S.#, and Gao, N.# (2015). HflX is a ribosome-splitting factor rescuing stalled ribosomes under stress conditions. Nat Struct Mol Biol 22, 906-913.

13.Zhang, D., Yan, K., Zhang, Y., Liu, G., Cao, X., Song, G., Xie, Q.#, Gao, N.#, and Qin, Y.# (2015). New insights into the enzymatic role of EF-G in ribosome recycling. Nucleic Acids Res 43, 10525-10533.

14.Ge, J., Li, W., Zhao, Q., Li, N., Chen, M., Zhi, P., Li, R., Gao, N.#, Xiao, B.#, and Yang, M.# (2015). Architecture of the mammalian mechanosensitive Piezo1 channel. Nature 527, 64-69.

15.Li, N., Zhai, Y.#, Zhang, Y., Li, W., Yang, M., Lei, J., Tye, B.K.#, and Gao, N#. (2015). Structure of the eukaryotic MCM complex at 3.8 A. Nature 524, 186-191.

·Highlighted in News & Views “DNA replication: Strand separation unraveled”;

·Recommended by “Faculty of 1000”, In F1000Prime, 19 Aug 2015; DOI: 10.3410/f.725681435.793508937

16.Zhang, Y., Ma, C., Yuan, Y., Zhu, J., Li, N., Chen, C., Wu, S., Yu, L., Lei, J.#, and Gao, N.# (2014). Structural basis for interaction of a cotranslational chaperone with the eukaryotic ribosome. Nat Struct Mol Biol 21, 1042-1046.

17.Zhang, X., Yan, K., Zhang, Y., Li, N., Ma, C., Li, Z., Zhang, Y., Feng, B., Liu, J., Sun, Y., Xu, Y., Lei, J.#, and Gao, N.# (2014). Structural insights into the function of a unique tandem GTPase EngA in bacterial ribosome assembly. Nucleic Acids Res 42, 13430-13439.

18.Feng, B., Mandava, C.S., Guo, Q., Wang, J., Cao, W., Li, N., Zhang, Y., Zhang, Y., Wang, Z., Wu, J., Sanyal, S.#, Lei, J.#, and Gao, N.# (2014). Structural and functional insights into the mode of action of a universally conserved Obg GTPase. PLoS Biol 12, e1001866.

·Highlighted in synopsis “Braking Bad: Stopping Translation in Hard Times”

19.Yang, Z., Guo, Q., Goto, S., Chen, Y., Li, N., Yan, K., Zhang, Y., Muto, A., Deng, H., Himeno, H., Lei, J.#, and Gao, N.# (2014). Structural insights into the assembly of the 30S ribosomal subunit in vivo: functional role of S5 and location of the 17S rRNA precursor sequence. Protein Cell 5, 394-407.

20.Liu, J., Mei, Z., Li, N., Qi, Y., Xu, Y., Shi, Y., Wang, F.#, Lei, J.#, and Gao, N.# (2013). Structural dynamics of the MecA-ClpC complex: a type II AAA+ protein unfolding machine. J Biol Chem 288, 17597-17608.

·Select by JBC editors as “Best Paper of the Year 2013” in molecular biophysics

21.Li, N., Chen, Y., Guo, Q., Zhang, Y., Yuan, Y., Ma, C., Deng, H., Lei, J.#, and Gao, N.# (2013). Cryo-EM structures of the late-stage assembly intermediates of the bacterial 50S ribosomal subunit. Nucleic Acids Res 41, 7073-7083.

22.Guo, Q., Goto, S., Chen, Y., Feng, B., Xu, Y., Muto, A., Himeno, H., Deng, H., Lei, J.#, and Gao, N.# (2013). Dissecting the in vivo assembly of the 30S ribosomal subunit reveals the role of RimM and general features of the assembly process. Nucleic Acids Res 41, 2609-2620.

23.Guo, Q., Yuan, Y., Xu, Y., Feng, B., Liu, L., Chen, K., Sun, M., Yang, Z., Lei, J.#, and Gao, N.# (2011). Structural basis for the function of a small GTPase RsgA on the 30S ribosomal subunit maturation revealed by cryoelectron microscopy. Proc Natl Acad Sci U S A 108, 13100-13105.

科研方向

高寧實驗室主要致力於闡明細胞內大型蛋白-核酸複合物形成的分子機器的精細結構及工作分子機制，近年來的科研工作著重於核糖體的生物生成（ribosome biogenesis）、蛋白質生物合成的調控、DNA複製起始調控等重要基礎生物學過程。實驗室主要採用冷凍電鏡三維重構的方法分析大型複合物的高分辨結構，輔助遺傳學、細胞生物學、生化分子生物學手段回答大分子機器在功能執行過程中的機制性問題。同時，針對結構課題中的技術難點，實驗室還致力於冷凍電鏡方法學的研究，包括樣品製備技術和演演算法的改進等。目前關注的一些基礎生物學領域包括：

1.Ribosome biogenesis and translation regulation.

2.Structure and mechanisms of DNA replication machinery.

3.Structural and functional study of Long non-coding RNA.