CV

Nadia Zatsepin

Professional experience

Affiliated with the Center for Biological Physics and Biodesign Center for Applied Structural Discovery at Arizona State University and the National Science Foundation BioXFEL Science and Technology Center.


Research summary

Publications: 62 refereed journal papers; over 8800 citations; h-index = 35 (Google Scholar,  April 2024).  Journals include Nature, Science, Cell, Nature Methods, Nature Communications, Nature Structural and Molecular Biology, Journal of the American Chemical Society, Proceedings of the National Academy of Sciences, an invited review article in Current Opinions in Structural Biology (2019), an invited book chapter on serial crystallography with XFELs (2018, Royal Soc. Chemistry), 3 refereed conference proceedings. Click here for full list of publications.

Research focusMy overarching research goal is to enable molecular movies with atomic resolution and ultrafast time resolution. We focus on the development and application of serial femtosecond crystallography (SFX) with X-ray free-electron lasers (XFELs), and serial crystallography with synchrotron and novel compact X-ray light sources. We work on novel algorithms/software, radiation damage and de novo phasing to obtain room-temperature structures of macromolecules, and to study their dynamics. One main target is a bacterial protein, disulphide bond-forming enzyme A, to aid in novel drug development to combat global antimicrobial resistance

Highlights and impact: Principal investigator on 4, and co-PI or collaborator on over 110 XFEL experiments. Corresponding senior author on the first membrane protein structure determination from a megahertz XFEL (Nature Communications 2019). Established a robust technique for high-resolution structure determination of G protein-coupled receptors and other membrane proteins from microcrystals at room-temperature: SFX in lipidic cubic phase (e.g. Fenalti, Zatsepin et al. Nature Struct. Mol. Biol. 2015). First SFX studies of ligand-binding activated reactions, observing large conformational changes in crystallo (Nature 2017), and real-time enzyme catalysis in microcrystals. First SFX studies observing femtosecond-scale dynamics of light-activated reactions with atomic resolution (Science 2014, 2015). Demonstrated proof-of-concept room-temperature serial microcrystallography at five microfocus synchrotron beamlines

Lead role: Over 2014-2019: Led serial crystallography data analysis in the National Science Foundation Science and Technology Center for Biology with X-ray Lasers (BioXFEL), a 10-year multi-US university consortium for the application and development of biological imaging with XFELs. 

Grants

I have been awarded over $3.2M  AUD  in research grants since 2015 as principal or co-principal investigator. (assuming 1 USD ~ 1.5 AUD). 


I was also a co-author on three large research centre grants as a senior investigator named in the grant:

-  NSF Science and Technology Center for Biology with X-ray Lasers, a consortium of eight US universities for the application and development of biological imaging with XFELs, awarded $25M USD for 2013 - 2018 ((PI: John C. H. Spence, ASU);

-  NSF BioXFEL STC renewal proposal, awarded $22.5M USD for 2018 - 2023 (PI: John C. H. Spence, ASU)

-  NSF Mid-scale Research Infrastructure-1 proposal for the design of a Compact X-ray Free-electron Laser at Arizona State University awarded $4.8M USD in 2019 (PI: William S. Graves, ASU).

Highlighted Publications

Click here for full list of publications.

(Updated May 2023)

1.     *** Gisriel, C., Coe, J., (74 more co-authors), Fromme, P., Zatsepin, N.A. (2019). Membrane protein megahertz crystallography at the European XFEL. Nature Commun. 10, 1–11.

Significance: World’s first structure determination of a large membrane protein (Photosystem I, key to photosynthesis in plants and some bacteria), using the world’s first ultra-high repetition rate X-ray laser. This was one of the largest membrane protein complexes ever studied with XFELs and the culmination of over a decade of technique and algorithm development. CrystFEL and DatView (see 6 and 8 below) were critical to this work.

2. Clabbers, M.T.B., Holmes, S., (14 more co-authors),  Zatsepin, N.A., Abbey, B., Sierecki, E., Gambin, Y., Stacey, K.J., Darmanin, C., Kobe, B., Xu, H., Ve, T. (2021) Nature Commun. 12, 1-14.

Significance: High-resolution structure determination comparing serial femtosecond crystallography and micro-electron diffraction from nano-scale crystals of the MyD88 TIR domain. MyD88 is involved in innate immune responses leading to pro-inflammatory cytokine production.

3. Tenboer, J., Basu, S., Zatsepin, N.A., (32 more co-authors), Schmidt, M. (2014). Time-resolved serial crystallography captures high-resolution intermediates of photoactive yellow protein. Science 346, 1242–1246.

Significance: The first molecular movie snapshots from an X-ray free-electron laser: studies of light-triggered dynamics of biomolecules with atomic resolution, which we then extended to femtosecond time resolution (i.e .the timescale of the initial photon capture) in Pande, et al. (2015). Femtosecond structural dynamics drives the trans/cis isomerization in photoactive yellow protein. Science 352, 725-729.

4.  Stagno, J.R., Liu, Y., Bhandari, Y.R., (30 more co-authors), Zatsepin, N.A., Chapman, H.N., Spence, J.C.H., Woodson, S.A., Wang, Y.-X., (2017). Structures of riboswitch RNA reaction states by mix-and-inject XFEL serial crystallography. Nature 541, 242–246.

Significance: In this world-first 'mix-and-inject' SFX experiment, we demonstrated that SFX can be used for structure determination during cyclic and non-cyclic reactions initiated by ligand binding, showing that, in some microcrystals, very large conformational changes are possible without loss of crystallinity.

5. Fenalti, G., Zatsepin, N.A., (32 more co-authors), Stevens, R.C., Cherezov, V., (2015). Structural basis for bifunctional peptide recognition at human δ-opioid receptor. Nat. Struct. Mol. Biol. 22, 265–268.

Significance: We determined a high-resolution, room-temperature structure of an opioid receptor involved in pain signalling with a bound peptide known to attenuate opioid side effects, providing a structural basis for (a) opioid receptor specificity and function, and (b) design of more effective, less addictive opioid-based drugs.

6.      ***   Stander, N., Fromme, P., Zatsepin, N.A., (2019). DatView: a graphical user interface for visualizing and querying large data sets in serial femtosecond crystallography. J. Appl. Cryst. 52, 1440–1448.

Significance: Python tool for multi-dimensional dataset exploration, which enables otherwise inaccessible feedback for data collection and facilitates data subset optimisation with an easy-to-use interface.

7. ***   Li, C., Li, X., Kirian, R., Spence, J.C.H., Liu, H., Zatsepin, N.A., (2019). SPIND: a reference-based auto-indexing algorithm for sparse serial crystallography data. IUCrJ. 6, 1, 72-84.

Significance: Robust new algorithm and open source software facilitating indexing snapshot serial crystallography patterns with > 4 Bragg spots, such as from small unit cells or weak patterns from crystals with larger unit cells. SPIND enabled the analysis of previously intractable data from ultrafast electronic damage studies.

8. White, T.A., Barty, A., Stellato, F., Holton, J.M., Kirian, R.A., Zatsepin, N.A., Chapman, H.N., (2013). Crystallographic data processing for free-electron laser sources. Acta Cryst. D 69, 1231–1240.

Significance: Description of data processing pipeline for XFEL serial crystallography: Cheetah (data reduction) and CrystFEL (indexing and merging); CrystFEL is the most widely used serial snapshot crystallography SFX analysis software worldwide, used for structure determination in 242 published papers (excluding reviews).

9. Zatsepin, N.A., Li, C., Colasurd, P., Nannenga, B.L., (2019). The complementarity of serial femtosecond crystallography and MicroED for structure determination from microcrystals. Curr. Op. Struct. Bio. 52, 1-8.

Significance: Invited review article. A concise comparison of two powerful, emerging techniques for high-resolution structure determination from macromolecular nano/microcrystals, SFX (using XFELs) or micro-electron diffraction (using transmission electron microscopes), emphasizing the techniques' complementary nature.

10.   *** Zatsepin, N. (2018). Crystallography with X-ray free electron lasers. In K. Beis and G. Evans (Eds.), Protein crystallography challenges and practical solutions (pp. 181–224).  Cambridge, UK: Royal Society of Chemistry.

Significance: Invited book chapter: Historical overview of serial femtosecond crystallography, new sample delivery technologies, the unique challenges and opportunities in SFX data collection and analysis, and a review of time-resolved pump-probe and mix-and-inject SFX results and ab initio phasing of SFX data to date.


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