Rie Nygaard, Ph.D.

Assistant Professor in Physiology and Biophysics

  • Assistant Professor in Physiology and Biophysics in Department of Radiation Oncology (primary appointment)

646-962-2096


 


Techniques

Research Areas

Research Summary:

In the Nygaard Lab, our primary focus is to elucidate how ionizing radiation affects cells at the molecular level. We employ structural biology techniques—including single-particle cryo-electron microscopy (cryo-EM)—alongside other biochemical and biophysical methods to study key targets involved in cellular responses to ionizing radiation. By understanding the fundamental biology of radiation therapy on a molecular scale, we aim to understand the differential responses observed in various cell types.

One of our main projects centers on uncovering the molecular mechanisms behind FLASH radiation therapy. FLASH is an innovative technique where radiation is delivered at ultra-high dose rates compared to conventional therapy, yet the total dose remains the same. Preclinical animal studies have shown that FLASH can significantly reduce toxicity in healthy tissues while preserving its effectiveness against tumors—a phenomenon known as the FLASH effect. The molecular basis of this effect is not yet fully understood. We aim to uncover the underlying molecular mechanisms of the FLASH effect to ultimately pave the way for safer and more effective radiation treatments.

Selected Publications:

  1. Liu Y, Brown CM, Erramilli S, Su YC, Tseng PS, Wang YJ, Duong NH, Tokarz P, Kloss B, Han CR, Chen HY, Rodrigues J, Archer M, Lowary TL, Kossiakoff AA, Stansfeld PJ, Nygaard R, Mancia F. Structural insights into terminal arabinosylation biosynthesis of the mycobacterial cell wall arabinan. bioRxiv. 2024 Sep 18;. doi: 10.1101/2024.09.17.613533. PubMed PMID: 39345558; PubMed Central PMCID: PMC11429727.
  2. Liu Y, Brown CM, Borges N, Nobre RN, Erramilli S, Dufrisne MB, Kloss B, Giacometti S, Esteves AM, Timoteo CG, Tokarz P, Cater R, Morita YS, Kossiakoff AA, Santos H, Stansfeld PJ, Nygaard R, Mancia F. Mechanistic studies of mycobacterial glycolipid biosynthesis by the mannosyltransferase PimE. bioRxiv. 2024 Sep 18;. doi: 10.1101/2024.09.17.613550. PubMed PMID: 39345506; PubMed Central PMCID: PMC11429742.
  3. Nygaard R, Graham CLB, Belcher Dufrisne M, Colburn JD, Pepe J, Hydorn MA, Corradi S, Brown CM, Ashraf KU, Vickery ON, Briggs NS, Deering JJ, Kloss B, Botta B, Clarke OB, Columbus L, Dworkin J, Stansfeld PJ, Roper DI, Mancia F. Structural basis of peptidoglycan synthesis by E. coli RodA-PBP2 complex. Nat Commun. 2023 Aug 24;14(1):5151. doi: 10.1038/s41467-023-40483-8. PubMed PMID: 37620344; PubMed Central PMCID: PMC10449877.
  4. Mani N, Nygaard R, Mancia F. Gone with the Wnt(less): a mechanistic perspective on the journey of Wnt. Biochem Soc Trans. 2022 Dec 16;50(6):1763-1772. doi: 10.1042/BST20220634. PubMed PMID: 36416660.
  5. Ashraf KU, Nygaard R, Vickery ON, Erramilli SK, Herrera CM, McConville TH, Petrou VI, Giacometti SI, Dufrisne MB, Nosol K, Zinkle AP, Graham CLB, Loukeris M, Kloss B, Skorupinska-Tudek K, Swiezewska E, Roper DI, Clarke OB, Uhlemann AC, Kossiakoff AA, Trent MS, Stansfeld PJ, Mancia F. Structural basis of lipopolysaccharide maturation by the O-antigen ligase. Nature. 2022 Apr;604(7905):371-376. doi: 10.1038/s41586-022-04555-x. Epub 2022 Apr 6. PubMed PMID: 35388216; PubMed Central PMCID: PMC9884178.
  6. Chai G, Szenker-Ravi E, Chung C, Li Z, Wang L, Khatoo M, Marshall T, Jiang N, Yang X, McEvoy-Venneri J, Stanley V, Anzenberg P, Lang N, Wazny V, Yu J, Virshup DM, Nygaard R, Mancia F, Merdzanic R, Toralles MBP, Pitanga PML, Puri RD, Hernan R, Chung WK, Bertoli-Avella AM, Al-Sannaa N, Zaki MS, Willert K, Reversade B, Gleeson JG. A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion. N Engl J Med. 2021 Sep 30;385(14):1292-1301. doi: 10.1056/NEJMoa2033911. PubMed PMID: 34587386; PubMed Central PMCID: PMC9017221.
  7. Nygaard R, Yu J, Kim J, Ross DR, Parisi G, Clarke OB, Virshup DM, Mancia F. Structural Basis of WLS/Evi-Mediated Wnt Transport and Secretion. Cell. 2021 Jan 7;184(1):194-206.e14. doi: 10.1016/j.cell.2020.11.038. Epub 2020 Dec 23. PubMed PMID: 33357447; PubMed Central PMCID: PMC7797000.
  8. Nygaard R, Kim J, Mancia F. Cryo-electron microscopy analysis of small membrane proteins. Curr Opin Struct Biol. 2020 Oct;64:26-33. doi: 10.1016/j.sbi.2020.05.009. Epub 2020 Jun 27. Review. PubMed PMID: 32603877; PubMed Central PMCID: PMC7665978.
  9. Nygaard R, Romaniuk JAH, Rice DM, Cegelski L. Whole Ribosome NMR: Dipolar Couplings and Contributions to Whole Cells. J Phys Chem B. 2017 Oct 12;121(40):9331-9335. doi: 10.1021/acs.jpcb.7b06736. Epub 2017 Sep 29. PubMed PMID: 28901760; PubMed Central PMCID: PMC5897578.
  10. Frimurer TM, Mende F, Graae AS, Engelstoft MS, Egerod KL, Nygaard R, Gerlach LO, Hansen JB, Schwartz TW, Holst B. Model-Based Discovery of Synthetic Agonists for the Zn(2+)-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions. J Med Chem. 2017 Feb 9;60(3):886-898. doi: 10.1021/acs.jmedchem.6b00648. Epub 2017 Jan 23. PubMed PMID: 28045522.
  11. Nygaard R, Romaniuk JAH, Rice DM, Cegelski L. Spectral snapshots of bacterial cell-wall composition and the influence of antibiotics by whole-cell NMR. Biophys J. 2015 Mar 24;108(6):1380-1389. doi: 10.1016/j.bpj.2015.01.037. PubMed PMID: 25809251; PubMed Central PMCID: PMC4375516.
  12. Nygaard R, Zou Y, Dror RO, Mildorf TJ, Arlow DH, Manglik A, Pan AC, Liu CW, Fung JJ, Bokoch MP, Thian FS, Kobilka TS, Shaw DE, Mueller L, Prosser RS, Kobilka BK. The dynamic process of β(2)-adrenergic receptor activation. Cell. 2013 Jan 31;152(3):532-42. doi: 10.1016/j.cell.2013.01.008. PubMed PMID: 23374348; PubMed Central PMCID: PMC3586676.
  13. Valentin-Hansen L, Groenen M, Nygaard R, Frimurer TM, Holliday ND, Schwartz TW. The arginine of the DRY motif in transmembrane segment III functions as a balancing micro-switch in the activation of the β2-adrenergic receptor. J Biol Chem. 2012 Sep 14;287(38):31973-82. doi: 10.1074/jbc.M112.348565. Epub 2012 Jul 26. PubMed PMID: 22843684; PubMed Central PMCID: PMC3442529.
  14. Nygaard R, Valentin-Hansen L, Mokrosinski J, Frimurer TM, Schwartz TW. Conserved water-mediated hydrogen bond network between TM-I, -II, -VI, and -VII in 7TM receptor activation. J Biol Chem. 2010 Jun 18;285(25):19625-36. doi: 10.1074/jbc.M110.106021. Epub 2010 Apr 15. PubMed PMID: 20395291; PubMed Central PMCID: PMC2885241.
  15. Holst B, Nygaard R, Valentin-Hansen L, Bach A, Engelstoft MS, Petersen PS, Frimurer TM, Schwartz TW. A conserved aromatic lock for the tryptophan rotameric switch in TM-VI of seven-transmembrane receptors. J Biol Chem. 2010 Feb 5;285(6):3973-3985. doi: 10.1074/jbc.M109.064725. Epub 2009 Nov 17. PubMed PMID: 19920139; PubMed Central PMCID: PMC2823539.
  16. Bokoch MP, Zou Y, Rasmussen SG, Liu CW, Nygaard R, Rosenbaum DM, Fung JJ, Choi HJ, Thian FS, Kobilka TS, Puglisi JD, Weis WI, Pardo L, Prosser RS, Mueller L, Kobilka BK. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature. 2010 Jan 7;463(7277):108-12. doi: 10.1038/nature08650. PubMed PMID: 20054398; PubMed Central PMCID: PMC2805469.
  17. Nygaard R, Frimurer TM, Holst B, Rosenkilde MM, Schwartz TW. Ligand binding and micro-switches in 7TM receptor structures. Trends Pharmacol Sci. 2009 May;30(5):249-59. doi: 10.1016/j.tips.2009.02.006. Epub 2009 Apr 16. Review. PubMed PMID: 19375807.
  18. Jensen PC, Nygaard R, Thiele S, Elder A, Zhu G, Kolbeck R, Ghosh S, Schwartz TW, Rosenkilde MM. Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8. Mol Pharmacol. 2007 Aug;72(2):327-40. doi: 10.1124/mol.106.035543. PubMed PMID: 17652183.
  19. Holst B, Mokrosinski J, Lang M, Brandt E, Nygaard R, Frimurer TM, Beck-Sickinger AG, Schwartz TW. Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism. J Biol Chem. 2007 May 25;282(21):15799-811. doi: 10.1074/jbc.M609796200. Epub 2007 Mar 19. PubMed PMID: 17371869.
  20. Rosenkilde MM, Andersen MB, Nygaard R, Frimurer TM, Schwartz TW. Activation of the CXCR3 chemokine receptor through anchoring of a small molecule chelator ligand between TM-III, -IV, and -VI. Mol Pharmacol. 2007 Mar;71(3):930-41. doi: 10.1124/mol.106.030031. Epub 2006 Dec 14. PubMed PMID: 17170198.