Skip to main content
SpringerLink
Log in

The precious fluorine on the ring: fluorine NMR for biological systems

  • Perspective
  • Published:
Journal of Biomolecular NMR Aims and scope Submit manuscript

Abstract

The fluorine-19 nucleus was recognized early to harbor exceptional properties for NMR spectroscopy. With 100% natural abundance, a high gyromagnetic ratio (83% sensitivity compared to 1H), a chemical shift that is extremely sensitive to its surroundings and near total absence in biological systems, it was destined to become a favored NMR probe, decorating small and large molecules. However, after early excitement, where uptake of fluorinated aromatic amino acids was explored in a series of animal studies, 19F-NMR lost popularity, especially in large molecular weight systems, due to chemical shift anisotropy (CSA) induced line broadening at high magnetic fields. Recently, two orthogonal approaches, (i) CF3 labeling and (ii) aromatic 19F-13C labeling leveraging the TROSY (Transverse Relaxation Optimized Spectroscopy) effect have been successfully applied to study large biomolecular systems. In this perspective, we will discuss the fascinating early work with fluorinated aromatic amino acids, which reveals the enormous potential of these non-natural amino acids in biological NMR and the potential of 19F-NMR to characterize protein and nucleic acid structure, function and dynamics in the light of recent developments. Finally, we explore how fluorine NMR might be exploited to implement small molecule or fragment screens that resemble physiological conditions and discuss the opportunity to follow the fate of small molecules in living cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abramov, G., Velyvis, A., Rennella, E., Wong, L.E. & Kay, L.E. A methyl-TROSY approach for NMR studies of high-molecular-weight DNA with application to the nucleosome core particle. Proc Natl Acad Sci U S A (2020).

  • Alderson TR, Kay LE (2020) Unveiling invisible protein states with NMR spectroscopy. Curr Opin Struct Biol 60:39–49

    Google Scholar 

  • Ardenkjaer-Larsen JH, Fridlund B, Gram A, Hansson G, Hansson L, Lerche MH, Servin R, Thaning M, Golman K (2003) Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR. Proc Natl Acad Sci U S A 100:10158–10163

    ADS  Google Scholar 

  • Arntson KE, Pomerantz WC (2016) Protein-Observed Fluorine NMR: A Bioorthogonal Approach for Small Molecule Discovery. J Med Chem 59:5158–5171

    Google Scholar 

  • Ayotte Y, Marando VM, Vaillancourt L, Bouchard P, Heffron G, Coote PW, Larda ST, LaPlante SR (2019) Exposing Small-Molecule Nanoentities by a Nuclear Magnetic Resonance Relaxation Assay. J Med Chem 62:7885–7896

    Google Scholar 

  • Bai J, Wang J, Ravula T, Im SC, Anantharamaiah GM, Waskell L, Ramamoorthy A (2020) Expression, purification, and functional reconstitution of (19)F-labeled cytochrome b5 in peptide nanodiscs for NMR studies. Biochim Biophys Acta Biomembr 1862:183194

    Google Scholar 

  • Ban D, Gossert AD, Giller K, Becker S, Griesinger C, Lee D (2012) Exceeding the limit of dynamics studies on biomolecules using high spin-lock field strengths with a cryogenically cooled probehead. J Magn Reson 221:1–4

    ADS  Google Scholar 

  • Ban D, Smith CA, de Groot BL, Griesinger C, Lee D (2017) Recent advances in measuring the kinetics of biomolecules by NMR relaxation dispersion spectroscopy. Arch Biochem Biophys 628:81–91

    Google Scholar 

  • Bao HL, Ishizuka T, Sakamoto T, Fujimoto K, Uechi T, Kenmochi N, Xu Y (2017) Characterization of human telomere RNA G-quadruplex structures in vitro and in living cells using 19F NMR spectroscopy. Nucleic Acids Res 45:5501–5511

    Google Scholar 

  • Barbieri L, Luchinat E, Banci L (2016) Characterization of proteins by in-cell NMR spectroscopy in cultured mammalian cells. Nat Protoc 11:1101–1111

    Google Scholar 

  • Bodsch W, Coenen HH, Stocklin G, Takahashi K, Hossmann KA (1988) Biochemical and autoradiographic study of cerebral protein synthesis with [18F]-and [14C]fluorophenylalanine. J Neurochem 50:979–983

    Google Scholar 

  • Boeszoermenyi A, Chhabra S, Dubey A, Radeva DL, Burdzhiev NT, Chanev CD, Petrov OI, Gelev VM, Zhang M, Anklin C, Kovacs H, Wagner G, Kuprov I, Takeuchi K, Arthanari H (2019) Aromatic (19)F-(13)C TROSY: a background-free approach to probe biomolecular structure, function, and dynamics. Nat Methods 16:333–340

    Google Scholar 

  • Bouvignies G, Kay LE (2012) A 2D (1)(3)C-CEST experiment for studying slowly exchanging protein systems using methyl probes: an application to protein folding. J Biomol NMR 53:303–310

    Google Scholar 

  • Carlomagno T, Amata I, Codutti L, Falb M, Fohrer J, Masiewicz P, Simon B (2013) Structural principles of RNA catalysis in a 2'-5' lariat-forming ribozyme. J Am Chem Soc 135:4403–4411

    Google Scholar 

  • Chaudhary, J., Bower, J. & Corbin, I.R. Lipoprotein Drug Delivery Vehicles for Cancer: Rationale and Reason. Int J Mol Sci20(2019).

  • Chrominski M, Baranowski MR, Chmielinski S, Kowalska J, Jemielity J (2020) Synthesis of Trifluoromethylated Purine Ribonucleotides and Their Evaluation as (19)F NMR Probes. J Org Chem 85:3440–3453

    Google Scholar 

  • Coenen HH, Kling P, Stocklin G (1989) Cerebral metabolism of L-[2-18F]fluorotyrosine, a new PET tracer of protein synthesis. J Nucl Med 30:1367–1372

    Google Scholar 

  • Cohen GN, Gros F (1960) PROTEIN BIOSYNTHESIS. Annu Rev Biochem 29:525–546

    Google Scholar 

  • Coote P, Anklin C, Massefski W, Wagner G, Arthanari H (2017) Rapid convergence of optimal control in NMR using numerically-constructed toggling frames. J Magn Reson 281:94–103

    ADS  Google Scholar 

  • Courtier-Murias D, Farooq H, Masoom H, Botana A, Soong R, Longstaffe JG, Simpson MJ, Maas WE, Fey M, Andrew B, Struppe J, Hutchins H, Krishnamurthy S, Kumar R, Monette M, Stronks HJ, Hume A, Simpson AJ (2012) Comprehensive multiphase NMR spectroscopy: basic experimental approaches to differentiate phases in heterogeneous samples. J Magn Reson 217:61–76

    ADS  Google Scholar 

  • Dalvit C, Ardini E, Flocco M, Fogliatto GP, Mongelli N, Veronesi M (2003) A general NMR method for rapid, efficient, and reliable biochemical screening. J Am Chem Soc 125:14620–14625

    Google Scholar 

  • Dalvit C, Mongelli N, Papeo G, Giordano P, Veronesi M, Moskau D, Kummerle R (2005b) Sensitivity improvement in 19F NMR-based screening experiments: theoretical considerations and experimental applications. J Am Chem Soc 127:13380–13385

    Google Scholar 

  • Dalvit C, Papeo G, Mongelli N, Giordano P, Saccardo B, Costa A, Veronesi M, Ko SY (2005a) Rapid NMR-based functional screening and IC50 measurements performed at unprecedentedly low enzyme concentration. Drug Dev Res 64:105–113

    Google Scholar 

  • Dalvit, C., Veronesi, M. & Vulpetti, A. Fluorine NMR functional screening: from purified enzymes to human intact living cells. J Biomol NMR (2020).

  • Dalvit C, Vulpetti A (2019) Ligand-Based Fluorine NMR Screening: Principles and Applications in Drug Discovery Projects. J Med Chem 62:2218–2244

    Google Scholar 

  • Danielson MA, Falke JJ (1996) Use of 19F NMR to probe protein structure and conformational changes. Annu Rev Biophys Biomol Struct 25:163–195

    Google Scholar 

  • Divakaran A, Kirberger SE, Pomerantz WCK (2019) SAR by (Protein-Observed) (19)F NMR. Acc Chem Res 52:3407–3418

    Google Scholar 

  • Durr UH, Grage SL, Witter R, Ulrich AS (2008) Solid state 19F NMR parameters of fluorine-labeled amino acids. Part I: aromatic substituents. J Magn Reson 191:7–15

    ADS  Google Scholar 

  • Franke B, Opitz C, Isogai S, Grahl A, Delgado L, Gossert AD, Grzesiek S (2018) Production of isotope-labeled proteins in insect cells for NMR. J Biomol NMR 71:173–184

    Google Scholar 

  • Garzo T, Hansson E, Ullberg S (1962) Uptake of C-14-para-fluorophenylalanine in the tissues of mice. Experientia 18:43–44

    Google Scholar 

  • Golman K, Ardenkjaer-Larsen JH, Petersson JS, Mansson S, Leunbach I (2003) Molecular imaging with endogenous substances. Proc Natl Acad Sci U S A 100:10435–10439

    ADS  Google Scholar 

  • Grage SL, Durr UH, Afonin S, Mikhailiuk PK, Komarov IV (2008) Ulrich, AS (2008) Solid state 19F NMR parameters of fluorine-labeled amino acids Part II: aliphatic substituents. J Magn Reson 191:16–23

    ADS  Google Scholar 

  • Gronenborn AM, Filpula DR, Essig NZ, Achari A, Whitlow M, Wingfield PT, Clore GM (1991) A novel, highly stable fold of the immunoglobulin binding domain of streptococcal protein G. Science 253:657–661

    ADS  Google Scholar 

  • Guillerez J, Lopez PJ, Proux F, Launay H, Dreyfus M (2005) A mutation in T7 RNA polymerase that facilitates promoter clearance. Proc Natl Acad Sci U S A 102:5958–5963

    ADS  Google Scholar 

  • Guo F, Li Q, Zhou C (2017) Synthesis and biological applications of fluoro-modified nucleic acids. Org Biomol Chem 15:9552–9565

    Google Scholar 

  • Hammann C, Norman DG, Lilley DM (2001) Dissection of the ion-induced folding of the hammerhead ribozyme using 19F NMR. Proc Natl Acad Sci U S A 98:5503–5508

    ADS  Google Scholar 

  • Hansson E, Garzo T (1962) Amino acid-analogue incorporation into pancreatic juice proteins in vivo. Biochim Biophys Acta 61:121–128

    Google Scholar 

  • Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, Schnitzer RJ, Pleven E, Scheiner J (1957) Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 179:663–666

    ADS  Google Scholar 

  • Hennig M, Munzarova ML, Bermel W, Scott LG, Sklenar V, Williamson JR (2006) Measurement of long-range 1H–19F scalar coupling constants and their glycosidic torsion dependence in 5-fluoropyrimidine-substituted RNA. J Am Chem Soc 128:5851–5858

    Google Scholar 

  • Hennig M, Scott LG, Sperling E, Bermel W, Williamson JR (2007) Synthesis of 5-fluoropyrimidine nucleotides as sensitive NMR probes of RNA structure. J Am Chem Soc 129:14911–14921

    Google Scholar 

  • Hewitt, R.I., Gumble, A.R., Taylor, L.H. & Wallace, W.S. The activity of a new antibiotic, nucleocidin, in experimental infections with Trypanosoma equiperdum. Antibiot Annu, 722–9 (1956).

  • Horowitz J, Ou CN, Ishaq M (1974) Isolation and partial characterization of Escherichia coli valine transfer RNA with uridine-derived residues replaced by 5-fluorouridine. J Mol Biol 88:301–312

    Google Scholar 

  • Horst R, Liu JJ, Stevens RC, Wüthrich K (2013) β2-Adrenergic receptor activation by agonists studied with 19F NMR spectroscopy. Angew Chem Int Ed 52:10762–10765

    Google Scholar 

  • Johnson JA, Nicolaou CA, Kirberger SE, Pandey AK, Hu H, Pomerantz WCK (2019) Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains. ACS Med Chem Lett 10:1648–1654

    Google Scholar 

  • Katrahalli U, Jaldappagari S, Kalanur SS (2010) Study of the interaction between fluoxetine hydrochloride and bovine serum albumin in the imitated physiological conditions by multi-spectroscopic methods. J Lumin 130:211–216

    Google Scholar 

  • Kay LE (2016) New Views of Functionally Dynamic Proteins by Solution NMR Spectroscopy. J Mol Biol 428:323–331

    Google Scholar 

  • Khan F, Kuprov I, Craggs TD, Hore PJ, Jackson SE (2006) 19F NMR studies of the native and denatured states of green fluorescent protein. J Am Chem Soc 128:10729–10737

    Google Scholar 

  • Kim H-W, Perez JA, Ferguson SJ, Campbell ID (1990) The specific incorporation of labelled aromatic amino acids into proteins through growth of bacteria in the presence of glyphosate. FEBS Lett 272:34–36

    Google Scholar 

  • Kim TH, Chung KY, Manglik A, Hansen AL, Dror RO, Mildorf TJ, Shaw DE, Kobilka BK, Prosser RS (2013) The role of ligands on the equilibria between functional states of a G Protein-Coupled receptor. J Am Chem Soc 135:9465–9474

    Google Scholar 

  • Kim, T.H., Mehrabi, P., Ren, Z., Sljoka, A., Ing, C., Bezginov, A., Ye, L., Pomes, R., Prosser, R.S. & Pai, E.F. The role of dimer asymmetry and protomer dynamics in enzyme catalysis. Science355(2017).

  • Kim Y, Hilty C (2015) Affinity screening using competitive binding with fluorine-19 hyperpolarized ligands. Angew Chem Int Ed Engl 54:4941–4944

    Google Scholar 

  • Kitevski-LeBlanc JL, Al-Abdul-Wahid MS, Prosser RS (2009a) A mutagenesis-free approach to assignment of (19)F NMR resonances in biosynthetically labeled proteins. J Am Chem Soc 131:2054–2055

    Google Scholar 

  • Kitevski-LeBlanc JL, Evanics F, Prosser RS (2009b) Approaches for the measurement of solvent exposure in proteins by 19F NMR. J Biomol NMR 45:255–264

    Google Scholar 

  • Kitevski-LeBlanc JL, Evanics F, Scott Prosser R (2010a) Optimizing FNMR protein spectroscopy by fractional biosynthetic labeling. J Biomol NMR 48:113–121

    Google Scholar 

  • Kitevski-LeBlanc JL, Evanics F, Scott Prosser R (2010b) Approaches to the assignment of 19F resonances from 3-fluorophenylalanine labeled calmodulin using solution state NMR. J Biomol NMR 47:113–123

    Google Scholar 

  • Kitevski-LeBlanc JL, Prosser RS (2012) Current applications of 19F NMR to studies of protein structure and dynamics. Prog Nucl Magn Reson Spectrosc 62:1–33

    Google Scholar 

  • Kiviniemi A, Virta P (2010) Characterization of RNA invasion by (19)F NMR spectroscopy. J Am Chem Soc 132:8560–8562

    Google Scholar 

  • Klimasauskas S, Szyperski T, Serva S, Wuthrich K (1998) Dynamic modes of the flipped-out cytosine during HhaI methyltransferase-DNA interactions in solution. EMBO J 17:317–324

    Google Scholar 

  • Kratz F (2008) Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release 132:171–183

    Google Scholar 

  • Krenzel ES, Chen Z, Hamilton JA (2013) Correspondence of fatty acid and drug binding sites on human serum albumin: a two-dimensional nuclear magnetic resonance study. Biochemistry 52:1559–1567

    Google Scholar 

  • Kreutz C, Kahlig H, Konrat R, Micura R (2006) A general approach for the identification of site-specific RNA binders by 19F NMR spectroscopy: proof of concept. Angew Chem Int Ed Engl 45:3450–3453

    Google Scholar 

  • Kreutz C, Nußbaumer F, Plangger R, Roeck M (2020) Aromatic 19F–13C TROSY - [19F, 13C] pyrimidine labeling for NMR spectroscopy of RNA. Angew Chem Int Ed Engl. https://doi.org/10.1002/anie.202006577

    Article  Google Scholar 

  • Kruh J, Rosa J (1959) Incorporation in vitro de [14C]fluorophénylalanine dans l'hémoglobine des réticulocytes de lapin. Biochem Biophys Acta 34:561–563

    Google Scholar 

  • Liu JJ, Horst R, Katritch V, Stevens RC, Wuthrich K (2012a) Biased signaling pathways in beta2-adrenergic receptor characterized by 19F-NMR. Science 335:1106–1110

    ADS  Google Scholar 

  • Liu L, Byeon IJ, Bahar I, Gronenborn AM (2012b) Domain swapping proceeds via complete unfolding: a 19F- and 1H-NMR study of the Cyanovirin-N protein. J Am Chem Soc 134:4229–4235

    Google Scholar 

  • Liu P, Sharon A, Chu CK (2008) Fluorinated Nucleosides: Synthesis and Biological Implication. J Fluor Chem 129:743–766

    Google Scholar 

  • Lu M, Wang M, Sergeyev IV, Quinn CM, Struppe J, Rosay M, Maas W, Gronenborn AM, Polenova T (2019) (19)F Dynamic nuclear polarization at fast magic angle spinning for nmr of hiv-1 capsid protein assemblies. J Am Chem Soc 141:5681–5691

    Google Scholar 

  • Maas WE, Laukien FH, Cory DG (1996) Gradient, High Resolution, Magic Angle Sample Spinning NMR. J Am Chem Soc 118:13085–13086

    Google Scholar 

  • Manglik A, Kim TH, Masureel M, Altenbach C, Yang Z, Hilger D, Lerch MT, Kobilka TS, Thian FS, Hubbell WL, Prosser RS, Kobilka BK (2015) Structural insights into the dynamic process of beta2-Adrenergic receptor signaling. Cell 161:1101–1111

    Google Scholar 

  • Marek M, Silvestro D, Fredslund MD, Andersen TG, Pomorski TG (2014) Serum albumin promotes ATP-binding cassette transporter-dependent sterol uptake in yeast. FEMS Yeast Res 14:1223–1233

    Google Scholar 

  • Mei H, Han J, Fustero S, Medio-Simon M, Sedgwick DM, Santi C, Ruzziconi R, Soloshonok VA (2019) Fluorine-Containing Drugs Approved by the FDA in 2018. Chemistry 25:11797–11819

    Google Scholar 

  • Milbradt AG, Arthanari H, Takeuchi K, Boeszoermenyi A, Hagn F, Wagner G (2015) Increased resolution of aromatic cross peaks using alternate 13C labeling and TROSY. J Biomol NMR 62:291–301

    Google Scholar 

  • Miskei M, Gregus A, Sharma R, Duro N, Zsolyomi F, Fuxreiter M (2017) Fuzziness enables context dependence of protein interactions. FEBS Lett 591:2682–2695

    Google Scholar 

  • Mulder FA, Skrynnikov NR, Hon B, Dahlquist FW, Kay LE (2001) Measurement of slow (micros-ms) time scale dynamics in protein side chains by (15)N relaxation dispersion NMR spectroscopy: application to Asn and Gln residues in a cavity mutant of T4 lysozyme. J Am Chem Soc 123:967–975

    Google Scholar 

  • Muller K, Faeh C, Diederich F (2007) Fluorine in pharmaceuticals: Looking beyond intuition. Science 317:1881–1886

    ADS  Google Scholar 

  • Munier R, Cohen GN (1959) Incorporation d'analogues structuraux d'aminoacides dans les protéines bactériennes au cours de leur synthèse in vivo. Biochem Biophys Acta 31:378–391

    Google Scholar 

  • Nikolaev Y, Ripin N, Soste M, Picotti P, Iber D, Allain FH (2019) Systems NMR: single-sample quantification of RNA, proteins and metabolites for biomolecular network analysis. Nat Methods 16:743–749

    Google Scholar 

  • Nogales E (2016) The development of cryo-EM into a mainstream structural biology technique. Nat Methods 13:24–27

    Google Scholar 

  • Nygaard R, Frimurer TM, Holst B, Rosenkilde MM, Schwartz TW (2009) Ligand binding and micro-switches in 7TM receptor structures. Trends Pharmacol Sci 30:249–259

    Google Scholar 

  • Olejniczak M, Gdaniec Z, Fischer A, Grabarkiewicz T, Bielecki L, Adamiak RW (2002) The bulge region of HIV-1 TAR RNA binds metal ions in solution. Nucleic Acids Res 30:4241–4249

    Google Scholar 

  • Palmer AG 3rd, Kroenke CD, Loria JP (2001) Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules. Methods Enzymol 339:204–238

    Google Scholar 

  • Papeo G, Giordano P, Brasca MG, Buzzo F, Caronni D, Ciprandi F, Mongelli N, Veronesi M, Vulpetti A, Dalvit C (2007) Polyfluorinated amino acids for sensitive 19F NMR-based screening and kinetic measurements. J Am Chem Soc 129:5665–5672

    Google Scholar 

  • Pervushin K, Riek R, Wider G, Wüthrich K (1998) Transverse Relaxation-Optimized Spectroscopy (TROSY) for NMR Studies of Aromatic Spin Systems in 13C-Labeled Proteins. J Am Chem Soc 120:6394–6400

    Google Scholar 

  • Pratihar S, Sabo TM, Ban D, Fenwick RB, Becker S, Salvatella X, Griesinger C, Lee D (2016) Kinetics of the Antibody Recognition Site in the Third IgG-Binding Domain of Protein G. Angew Chem Int Ed Engl 55:9567–9570

    Google Scholar 

  • Pritisanac I, Degiacomi MT, Alderson TR, Carneiro MG, Ab E, Siegal G, Baldwin AJ (2017) Automatic Assignment of Methyl-NMR Spectra of Supramolecular Machines Using Graph Theory. J Am Chem Soc 139:9523–9533

    Google Scholar 

  • Pritisanac I, Wurz JM, Alderson TR, Guntert P (2019) Automatic structure-based NMR methyl resonance assignment in large proteins. Nat Commun 10:4922

    ADS  Google Scholar 

  • Puffer B, Kreutz C, Rieder U, Ebert MO, Konrat R, Micura R (2009) 5-Fluoro pyrimidines: labels to probe DNA and RNA secondary structures by 1D 19F NMR spectroscopy. Nucleic Acids Res 37:7728–7740

    Google Scholar 

  • Qiu X-L, Xu X-H, Qing F-L (2010) Recent advances in the synthesis of fluorinated nucleosides. Tetrahedron 66:789–843

    Google Scholar 

  • Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE, Moore KJ (2011) Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478:404–407

    ADS  Google Scholar 

  • Reddy JG, Pratihar S, Ban D, Frischkorn S, Becker S, Griesinger C, Lee D (2018) Simultaneous determination of fast and slow dynamics in molecules using extreme CPMG relaxation dispersion experiments. J Biomol NMR 70:1–9

    Google Scholar 

  • Richmond MH (1960) Incorporation of dl-beta-(p-fluorophenyl)[beta-C]alanine into exopenicillinase by Bacillus cereus 569/H. Biochem J 77:121–135

    Google Scholar 

  • Rizvi NF, Santa Maria JP, Nahvi A, Klappenbach J, Klein DJ, Curran PJ, Richards MP, Chamberlin C, Saradjian P, Burchard J, Aguilar R, Lee JT, Dandliker PJ, Smith GF, Kutchukian P, Nickbarg EB (2020) Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like Chemical Space. SLAS Discov 25:384–396

    Google Scholar 

  • Roos M, Mandala VS, Hong M (2018) Determination of Long-Range Distances by Fast Magic-Angle-Spinning Radiofrequency-Driven (19)F-(19)F Dipolar Recoupling NMR. J Phys Chem B 122:9302–9313

    Google Scholar 

  • Roth BD (2002) The discovery and development of atorvastatin, a potent novel hypolipidemic agent. Prog Med Chem 40:1–22

    Google Scholar 

  • Schnieders, R., Keyhani, S., Schwalbe, H. & Fürtig, B. More than Proton Detection—New Avenues for NMR Spectroscopy of RNA. Chemistry – A European Journal26, 102–113 (2020).

  • Schuler B, Kremer W, Kalbitzer HR, Jaenicke R (2002) Role of entropy in protein thermostability: folding kinetics of a hyperthermophilic cold shock protein at high temperatures using 19F NMR. Biochemistry 41:11670–11680

    Google Scholar 

  • Scott LG, Geierstanger BH, Williamson JR, Hennig M (2004) Enzymatic synthesis and 19F NMR studies of 2-fluoroadenine-substituted RNA. J Am Chem Soc 126:11776–11777

    Google Scholar 

  • Scott, L.G. & Hennig, M. Chapter Three - 19F-Site-Specific-Labeled Nucleotides for Nucleic Acid Structural Analysis by NMR. in Methods in Enzymology, Vol. 566 (ed. Kelman, Z.) 59–87 (Academic Press, 2016).

  • Simpson, A.J., Courtier-Murias, D., Longstaffe, J.G., Masoom, H., Soong, R., Lam, L., Sutrisno, A., Farooq, H., Simpson, M.J., Maas, W.E., Fey, M., Andrew, B., Struppe, J., Hutchins, H., Krishnamurthy, S., Kumar, R., Monette, M. & Stronks, H.J. (2013) Environmental Comprehensive Multiphase NMR. eMagRes, 399–414

  • Smith CA, Ban D, Pratihar S, Giller K, Schwiegk C, de Groot BL, Becker S, Griesinger C, Lee D (2015) Population shuffling of protein conformations. Angew Chem Int Ed Engl 54:207–210

    Google Scholar 

  • Sochor F, Silvers R, Muller D, Richter C, Furtig B, Schwalbe H (2016) (19)F-labeling of the adenine H2-site to study large RNAs by NMR spectroscopy. J Biomol NMR 64:63–74

    Google Scholar 

  • Sprangers R, Li X, Mao X, Rubinstein JL, Schimmer AD, Kay LE (2008) TROSY-based NMR evidence for a novel class of 20S proteasome inhibitors. Biochemistry 47:6727–6734

    Google Scholar 

  • Tokunaga, Y., Viennet, T., Arthanari, H. & Takeuchi, K. Spotlight on the Ballet of Proteins: The Structural Dynamic Properties of Proteins Illuminated by Solution NMR. Int J Mol Sci21(2020).

  • Toptygin D, Gronenborn AM, Brand L (2006) Nanosecond relaxation dynamics of protein GB1 identified by the time-dependent red shift in the fluorescence of tryptophan and 5-fluorotryptophan. J Phys Chem B 110:26292–26302

    Google Scholar 

  • Urick AK, Hawk LM, Cassel MK, Mishra NK, Liu S, Adhikari N, Zhang W, dos Santos CO, Hall JL, Pomerantz WC (2015) Dual Screening of BPTF and Brd4 Using Protein-Observed Fluorine NMR Uncovers New Bromodomain Probe Molecules. ACS Chem Biol 10:2246–2256

    Google Scholar 

  • Vallurupalli P, Bouvignies G, Kay LE (2012) Studying "invisible" excited protein states in slow exchange with a major state conformation. J Am Chem Soc 134:8148–8161

    Google Scholar 

  • Vaughan M, Steinberg D (1960) Biosynthetic incorporation of fluorophenylalanine into crystalline proteins. Biochem Biophys Acta 40:230–236

    Google Scholar 

  • Venkatakrishnan AJ, Deupi X, Lebon G, Heydenreich FM, Flock T, Miljus T, Balaji S, Bouvier M, Veprintsev DB, Tate CG, Schertler GF, Babu MM (2016) Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region. Nature 536:484–487

    ADS  Google Scholar 

  • Wang M, Lu M, Fritz MP, Quinn CM, Byeon IL, Byeon CH, Struppe J, Maas W, Gronenborn AM, Polenova T (2018) Fast Magic-Angle Spinning (19) F NMR Spectroscopy of HIV-1 Capsid Protein Assemblies. Angew Chem Int Ed Engl 57:16375–16379

    Google Scholar 

  • Wang Q, Huang CR, Jiang M, Zhu YY, Wang J, Chen J, Shi JH (2016) Binding interaction of atorvastatin with bovine serum albumin: Spectroscopic methods and molecular docking. Spectrochim Acta A Mol Biomol Spectrosc 156:155–163

    ADS  Google Scholar 

  • Watts JK, Martin-Pintado N, Gomez-Pinto I, Schwartzentruber J, Portella G, Orozco M, Gonzalez C, Damha MJ (2010) Differential stability of 2'F-ANA*RNA and ANA*RNA hybrid duplexes: roles of structure, pseudohydrogen bonding, hydration, ion uptake and flexibility. Nucleic Acids Res 38:2498–2511

    Google Scholar 

  • Waudby CA, Ramos A, Cabrita LD, Christodoulou J (2016) Two-Dimensional NMR Lineshape Analysis. Sci Rep 6:24826

    ADS  Google Scholar 

  • Weissman A, Koe BK (1967) m-Fluorotyrosine convulsions and mortality: relationship to catecholamine and citrate metabolism. J Pharmacol Exp Ther 155:135–144

    Google Scholar 

  • Westhead EW, Boyer PD (1961) The incorporation of p-fluorophenylalanine into some rabbit enzymes and other proteins. Biochem Biophys Acta 54:145–156

    Google Scholar 

  • Wilton DJ, Tunnicliffe RB, Kamatari YO, Akasaka K, Williamson MP (2008) Pressure-induced changes in the solution structure of the GB1 domain of protein G. Proteins 71:1432–1440

    Google Scholar 

  • Wong DT, Bymaster FP, Engleman EA (1995) Prozac (fluoxetine, lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: Twenty years since its first publication. Life Sci 57:411–441

    Google Scholar 

  • Yang F, Yu X, Liu C, Qu C-X, Gong Z, Liu H-D, Li F-H, Wang H-M, He D-F, Yi F, Song C, Tian C-L, Xiao K-H, Wang J-Y, Sun J-P (2015) Phospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and 19F-NMR. Nat Commun 6:8202

    ADS  Google Scholar 

  • Yang F, Zhang Y, Liang H (2014) Interactive association of drugs binding to human serum albumin. Int J Mol Sci 15:3580–3595

    Google Scholar 

  • Ycas PD, Wagner N, Olsen NM, Fu R, Pomerantz WCK (2020) 2-Fluorotyrosine is a valuable but understudied amino acid for protein-observed (19)F NMR. J Biomol NMR 74:61–69

    Google Scholar 

  • Ye L, Van Eps N, Zimmer M, Ernst OP, Prosser RS (2016) Activation of the A2A adenosine G-protein-coupled receptor by conformational selection. Nature 533:265–268

    ADS  Google Scholar 

  • Yoshida A (1960) Studies on the mechanism of protein synthesis; Incorporation of p-fluorophenylalanine into α-amylase of Bacillus subtilis. Biochem Biophys Acta 41:98–103

    Google Scholar 

Download references

Acknowledgements

The authors would like to thank Gregory Heffron (Associate in Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA) and the East Quad NMR Facility at Harvard Medical School, as well as Clemens Anklin (Bruker Biospin, Billerica, MA, USA), for assistance with fluorine NMR. The authors are especially grateful to Vladimir M. Gelev (Faculty of Chemistry and Pharmacy, Sofia University, Sofia, Bulgaria) for the synthesis of 19F-13C-labeled 3-fluorotyrosine, to Sandeep Chhabra (Amgen, CA, USA) for the expression and purification of the proteasome a7 single-ring subunit, to L.E. Kay (Departments of Molecular Genetics, Biochemistry, and Chemistry, University of Toronto, Toronto, Ontario, Canada) for sharing the plasmid carrying the single-ring α7 proteasome particle with us and to Helena Kovacs (Bruker Biospin, Fällanden, Switzerland) for discussions regarding the work.

Funding

This research was supported by the NIH grant GM129026 to G.W. and NIH grant GM136859 to H.A. A.B. acknowledges funding from the American Heart Association’s fellowship 19POST34380800 and the Austrian Science Fund’s Schrödinger Fellowship J3872-B21. H.A. thanks the Claudia Adams Barr Program for Innovative Cancer Research for support.

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Andras Boeszoermenyi, Akshay Jain & Haribabu Arthanari

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA, 02115, USA

    Andras Boeszoermenyi, Haribabu Arthanari & Gerhard Wagner

  3. Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital and, Harvard Medical School, Boston, MA, 02115, USA

    Barbara Ogórek

Authors
  1. Andras Boeszoermenyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Ogórek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akshay Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haribabu Arthanari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gerhard Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.B., B.O and H.A. designed research; A.B., B.O and A.J. performed experiments; A.B. analyzed data., and A.B, H.A. and G.W. wrote the manuscript.

Corresponding authors

Correspondence to Andras Boeszoermenyi or Gerhard Wagner.

Ethics declarations

Conflict of interest

The authors declare no conflicts or competing financial interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boeszoermenyi, A., Ogórek, B., Jain, A. et al. The precious fluorine on the ring: fluorine NMR for biological systems. J Biomol NMR 74, 365–379 (2020). https://doi.org/10.1007/s10858-020-00331-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10858-020-00331-z

Keywords

Search

Navigation