NMR Spectroscopy in the Analysis of Protein-Protein Interactions

  • David A. Gell
  • Ann H. Kwan
  • Joel P. Mackay
Reference work entry


Protein-protein interactions are a central aspect of biology and NMR spectroscopy is one of the most powerful and versatile methods available to characterize their structure, dynamics, kinetics and thermodynamics. In this article, we give an overview of the suite of approaches available to the researcher who wishes to understand their favourite protein-protein interaction in more detail. We begin with an outline of two fundamental concepts that are important for understanding the strengths and limitations of NMR spectroscopy – nuclear spin relaxation and chemical exchange. We then present a range of methods including chemical shift perturbation analysis, nuclear Overhauser effects (and its derivatives), residual dipolar couplings, paramagnetic approaches, solid-state NMR and the analysis of low-abundance species. Each method is accompanied by recen texamples from the literature. Together, these techniques can allow both broad and deep insight into the mechanistic underpinnings of protein-protein interactions.


Chemical exchange Chemical shift perturbation Cross-saturation Dark states Macromolecular NMR spectroscopy Methyl-TROSY Protein complexes Protein-protein interactions 


  1. 1.
    Gardner KH, Kay LE. The use of 2H, 13C, 15N multidimensional NMR to study the structure and dynamics of proteins. Annu Rev Biophys Biomol Struct. 1998;27:357–406.CrossRefGoogle Scholar
  2. 2.
    Pervushin K. Impact of transverse relaxation optimized spectroscopy (TROSY) on NMR as a technique in structural biology. Q Rev Biophys. 2000;33:161–97.CrossRefGoogle Scholar
  3. 3.
    Roberts G. Structural and dynamic information on ligand binding. In: Lian L, Roberts G, editors. Protein NMR spectroscopy: practical techniques and applications. Hoboken: Wiley; 2011. p. 221–67.CrossRefGoogle Scholar
  4. 4.
    Schreiber G. Kinetic studies of protein-protein interactions. Curr Opin Struct Biol. 2002;12:41–7.CrossRefGoogle Scholar
  5. 5.
    Williamson MP. Using chemical shift perturbation to characterise ligand binding. Prog Nucl Magn Reson Spectrosc. 2013;73:1–16.CrossRefGoogle Scholar
  6. 6.
    Luna RE, Akabayov SR, Ziarek JJ, Wagner G. Examining weak protein-protein interactions in start codon recognition via NMR spectroscopy. FEBS J. 2014;281:1965–73.CrossRefGoogle Scholar
  7. 7.
    Bauer F, Schweimer K, Meiselbach H, Hoffmann S, Rosch P, Sticht H. Structural characterization of Lyn-SH3 domain in complex with a herpesviral protein reveals an extended recognition motif that enhances binding affinity. Protein Sci. 2005;14:2487–98.CrossRefGoogle Scholar
  8. 8.
    Huang X, Yang X, Luft BJ, Koide S. NMR identification of epitopes of Lyme disease antigen OspA to monoclonal antibodies. J Mol Biol. 1998;281:61–7.CrossRefGoogle Scholar
  9. 9.
    Malia TJ, Wagner G. NMR structural investigation of the mitochondrial outer membrane protein VDAC and its interaction with antiapoptotic Bcl-xL. Biochemistry. 2007;46:514–25.CrossRefGoogle Scholar
  10. 10.
    Ozawa S, Kimura T, Nozaki T, Harada H, Shimada I, Osawa M. Structural basis for the inhibition of voltage-dependent K+ channel by gating modifier toxin. Sci Rep. 2015;5:14226.CrossRefGoogle Scholar
  11. 11.
    Zhang M, Huang R, Ackermann R, Im SC, Waskell L, Schwendeman A, Ramamoorthy A. Reconstitution of the Cytb5-CytP450 complex in nanodiscs for structural studies using NMR spectroscopy. Angew Chem Int Ed Engl. 2016;55:4497–9.CrossRefGoogle Scholar
  12. 12.
    Fiaux J, Bertelsen EB, Horwich AL, Wuthrich K. NMR analysis of a 900K GroEL GroES complex. Nature. 2002;418:207–11.CrossRefGoogle Scholar
  13. 13.
    Sugase K, Dyson HJ, Wright PE. Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature. 2007;447:1021–5.CrossRefGoogle Scholar
  14. 14.
    Montalvao RW, Cavalli A, Salvatella X, Blundell TL, Vendruscolo M. Structure determination of protein-protein complexes using NMR chemical shifts: case of an endonuclease colicin-immunity protein complex. J Am Chem Soc. 2008;130:15990–6.CrossRefGoogle Scholar
  15. 15.
    Shen Y, Lange O, Delaglio F, Rossi P, Aramini JM, Liu G, Eletsky A, Wu Y, Singarapu KK, Lemak A, et al. Consistent blind protein structure generation from NMR chemical shift data. Proc Natl Acad Sci U S A. 2008;105:4685–90.CrossRefGoogle Scholar
  16. 16.
    Tugarinov V, Hwang PM, Ollerenshaw JE, Kay LE. Cross-correlated relaxation enhanced 1H[bond]13C NMR spectroscopy of methyl groups in very high molecular weight proteins and protein complexes. J Am Chem Soc. 2003;125:10420–8.CrossRefGoogle Scholar
  17. 17.
    Gelis I, Bonvin AM, Keramisanou D, Koukaki M, Gouridis G, Karamanou S, Economou A, Kalodimos CG. Structural basis for signal-sequence recognition by the translocase motor SecA as determined by NMR. Cell. 2007;131:756–69.CrossRefGoogle Scholar
  18. 18.
    Gardner K, Kay L. Production and incorporation of 15N, 13C, 2H (1H-δ1 methyl) isoleucine into proteins for multidimensional NMR studies. J Am Chem Soc. 1997;119:7599–600.CrossRefGoogle Scholar
  19. 19.
    Goto NK, Gardner KH, Mueller GA, Willis RC, Kay LE. A robust and cost-effective method for the production of Val, Leu, Ile (delta 1) methyl-protonated 15N-, 13C-, 2H-labeled proteins. J Biomol NMR. 1999;13:369–74.CrossRefGoogle Scholar
  20. 20.
    Gobl C, Madl T, Simon B, Sattler M. NMR approaches for structural analysis of multidomain proteins and complexes in solution. Prog Nucl Magn Reson Spectrosc. 2014;80:26–63.CrossRefGoogle Scholar
  21. 21.
    Milbradt AG, Arthanari H, Takeuchi K, Boeszoermenyi A, Hagn F, Wagner G. Increased resolution of aromatic cross peaks using alternate 13C labeling and TROSY. J Biomol NMR. 2015;62:291–301.CrossRefGoogle Scholar
  22. 22.
    Kerfah R, Plevin MJ, Sounier R, Gans P, Boisbouvier J. Methyl-specific isotopic labeling: a molecular tool box for solution NMR studies of large proteins. Curr Opin Struct Biol. 2015;32:113–22.CrossRefGoogle Scholar
  23. 23.
    Zhang H, van Ingen H. Isotope-labeling strategies for solution NMR studies of macromolecular assemblies. Curr Opin Struct Biol. 2016;38:75–82.CrossRefGoogle Scholar
  24. 24.
    Sprangers R, Kay LE. Quantitative dynamics and binding studies of the 20S proteasome by NMR. Nature. 2007;445:618–22.CrossRefGoogle Scholar
  25. 25.
    Huang C, Rossi P, Saio T, Kalodimos CG. Structural basis for the antifolding activity of a molecular chaperone. Nature. 2016;537:202–6.CrossRefGoogle Scholar
  26. 26.
    Saio T, Guan X, Rossi P, Economou A, Kalodimos CG. Structural basis for protein antiaggregation activity of the trigger factor chaperone. Science. 2014;344:1250494.CrossRefGoogle Scholar
  27. 27.
    Krois AS, Ferreon JC, Martinez-Yamout MA, Dyson HJ, Wright PE. Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein. Proc Natl Acad Sci U S A. 2016;113:E1853–62.CrossRefGoogle Scholar
  28. 28.
    Kato H, van Ingen H, Zhou BR, Feng H, Bustin M, Kay LE, Bai Y. Architecture of the high mobility group nucleosomal protein 2-nucleosome complex as revealed by methyl-based NMR. Proc Natl Acad Sci U S A. 2011;108:12283–8.CrossRefGoogle Scholar
  29. 29.
    Stoffregen MC, Schwer MM, Renschler FA, Wiesner S. Methionine scanning as an NMR tool for detecting and analyzing biomolecular interaction surfaces. Structure. 2012;20:573–81.CrossRefGoogle Scholar
  30. 30.
    Lian LY. NMR studies of weak protein-protein interactions. Prog Nucl Magn Reson Spectrosc. 2013;71:59–72.CrossRefGoogle Scholar
  31. 31.
    Teilum K, Kunze MB, Erlendsson S. Kragelund BB: (S)Pinning down protein interactions by NMR. Protein Sci. 2017;26:436–51.CrossRefGoogle Scholar
  32. 32.
    Markin CJ, Spyracopoulos L. Accuracy and precision of protein-ligand interaction kinetics determined from chemical shift titrations. J Biomol NMR. 2012;54:355–76.CrossRefGoogle Scholar
  33. 33.
    Markin CJ, Spyracopoulos L. Increased precision for analysis of protein-ligand dissociation constants determined from chemical shift titrations. J Biomol NMR. 2012;53:125–38.CrossRefGoogle Scholar
  34. 34.
    Arai M, Ferreon JC, Wright PE. Quantitative analysis of multisite protein-ligand interactions by NMR: binding of intrinsically disordered p53 transactivation subdomains with the TAZ2 domain of CBP. J Am Chem Soc. 2012;134:3792–803.CrossRefGoogle Scholar
  35. 35.
    Ferreon JC, Lee CW, Arai M, Martinez-Yamout MA, Dyson HJ, Wright PE. Cooperative regulation of p53 by modulation of ternary complex formation with CBP/p300 and HDM2. Proc Natl Acad Sci U S A. 2009;106:6591–6.CrossRefGoogle Scholar
  36. 36.
    Suh JY, Cai M, Williams Jr DC, Clore GM. Solution structure of a post-transition state analog of the phosphotransfer reaction between the A and B cytoplasmic domains of the mannitol transporter IIMannitol of the Escherichia coli phosphotransferase system. J Biol Chem. 2006;281:8939–49.CrossRefGoogle Scholar
  37. 37.
    Feeney J, Batchelor J, Albrand J, Roberts G. The effects of intermediate exchange processes on the estimation of equilibrium constants by NMR. J Magn Reson. 1979;33:519–29.Google Scholar
  38. 38.
    Kowalski K, Liew CK, Matthews JM, Gell DA, Crossley M, Mackay JP. Characterization of the conserved interaction between GATA and FOG family proteins. J Biol Chem. 2002;277:35720–9.CrossRefGoogle Scholar
  39. 39.
    Kovrigin EL. NMR line shapes and multi-state binding equilibria. J Biomol NMR. 2012;53:257–70.CrossRefGoogle Scholar
  40. 40.
    London RE. Chemical-shift and linewidth characteristics of reversibly bound ligands. J Magn Reson A. 1993;104:190–6.CrossRefGoogle Scholar
  41. 41.
    Waudby CA, Ramos A, Cabrita LD, Christodoulou J. Two-dimensional NMR lineshape analysis. Sci Rep. 2016;6:24826.CrossRefGoogle Scholar
  42. 42.
    Lisi GP, Loria JP. Solution NMR spectroscopy for the study of Enzyme allostery. Chem Rev. 2016;116:6323–69.CrossRefGoogle Scholar
  43. 43.
    Konuma T, Lee YH, Goto Y, Sakurai K. Principal component analysis of chemical shift perturbation data of a multiple-ligand-binding system for elucidation of respective binding mechanism. Proteins. 2013;81:107–18.CrossRefGoogle Scholar
  44. 44.
    Schilder J, Ubbink M. Formation of transient protein complexes. Curr Opin Struct Biol. 2013;23:911–8.CrossRefGoogle Scholar
  45. 45.
    Volkov AN, Ferrari D, Worrall JA, Bonvin AM, Ubbink M. The orientations of cytochrome c in the highly dynamic complex with cytochrome b5 visualized by NMR and docking using HADDOCK. Protein Sci. 2005;14:799–811.CrossRefGoogle Scholar
  46. 46.
    Worrall JA, Liu Y, Crowley PB, Nocek JM, Hoffman BM, Ubbink M. Myoglobin and cytochrome b5: a nuclear magnetic resonance study of a highly dynamic protein complex. Biochemistry. 2002;41:11721–30.CrossRefGoogle Scholar
  47. 47.
    Stollar EJ, Lin H, Davidson AR, Forman-Kay JD. Differential dynamic engagement within 24 SH3 domain: peptide complexes revealed by co-linear chemical shift perturbation analysis. PLoS One. 2012;7:e51282.CrossRefGoogle Scholar
  48. 48.
    Selvaratnam R, Chowdhury S, VanSchouwen B, Melacini G. Mapping allostery through the covariance analysis of NMR chemical shifts. Proc Natl Acad Sci U S A. 2011;108:6133–8.CrossRefGoogle Scholar
  49. 49.
    Masterson LR, Yu T, Shi L, Wang Y, Gustavsson M, Mueller MM, Veglia G. cAMP-dependent protein kinase A selects the excited state of the membrane substrate phospholamban. J Mol Biol. 2011;412:155–64.CrossRefGoogle Scholar
  50. 50.
    Kwan AH, Mobli M, Gooley PR, King GF, Mackay JP. Macromolecular NMR spectroscopy for the non-spectroscopist. FEBS J. 2011;278:687–703.CrossRefGoogle Scholar
  51. 51.
    Guntert P, Buchner L. Combined automated NOE assignment and structure calculation with CYANA. J Biomol NMR. 2015;62:453–71.CrossRefGoogle Scholar
  52. 52.
    Guntert P, Mumenthaler C, Wuthrich K. Torsion angle dynamics for NMR structure calculation with the new program DYANA. J Mol Biol. 1997;273:283–98.CrossRefGoogle Scholar
  53. 53.
    Schwieters CD, Kuszewski JJ, Clore GM. Using Xplor-NIH for NMR molecular structure determination. Prog Nucl Magn Reson Spectrosc. 2006;48:47–62.CrossRefGoogle Scholar
  54. 54.
    Schwieters CD, Kuszewski JJ, Tjandra N, Clore GM. The Xplor-NIH NMR molecular structure determination package. J Magn Reson. 2003;160:65–73.CrossRefGoogle Scholar
  55. 55.
    Brunger AT. Version 1.2 of the crystallography and NMR system. Nat Protoc. 2007;2:2728–33.CrossRefGoogle Scholar
  56. 56.
    Rieping W, Habeck M, Bardiaux B, Bernard A, Malliavin TE, Nilges M. ARIA2: automated NOE assignment and data integration in NMR structure calculation. Bioinformatics. 2007;23:381–2.CrossRefGoogle Scholar
  57. 57.
    van Zundert GCP, Melquiond ASJ, Bonvin AMJJ. Integrative modeling of biomolecular complexes: HADDOCKing with Cryo-electron microscopy data. Structure. 2015;23:949–60.CrossRefGoogle Scholar
  58. 58.
    van Zundert GC, Rodrigues JP, Trellet M, Schmitz C, Kastritis PL, Karaca E, Melquiond AS, van Dijk M, de Vries SJ, Bonvin AM. The HADDOCK2.2 Web server: user-friendly integrative modeling of biomolecular complexes. J Mol Biol. 2016;428:720–5.CrossRefGoogle Scholar
  59. 59.
    Karaca E, Bonvin AM. Advances in integrative modeling of biomolecular complexes. Methods. 2013;59:372–81.CrossRefGoogle Scholar
  60. 60.
    van Ingen H, Bonvin AM. Information-driven modeling of large macromolecular assemblies using NMR data. J Magn Reson. 2014;241:103–14.CrossRefGoogle Scholar
  61. 61.
    Vogeli B. The nuclear Overhauser effect from a quantitative perspective. Prog Nucl Magn Reson Spectrosc. 2014;78:1–46.CrossRefGoogle Scholar
  62. 62.
    Anglister J, Srivastava G, Naider F. Detection of intermolecular NOE interactions in large protein complexes. Prog Nucl Magn Reson Spectrosc. 2016;97:40–56.CrossRefGoogle Scholar
  63. 63.
    Nudelman I, Akabayov SR, Schnur E, Biron Z, Levy R, Xu Y, Yang D, Anglister J. Intermolecular interactions in a 44 kDa interferon-receptor complex detected by asymmetric reverse-protonation and two-dimensional NOESY. Biochemistry. 2010;49:5117–33.CrossRefGoogle Scholar
  64. 64.
    Nudelman I, Akabayov SR, Scherf T, Anglister J. Observation of intermolecular interactions in large protein complexes by 2D-double difference nuclear Overhauser enhancement spectroscopy: application to the 44 kDa interferon-receptor complex. J Am Chem Soc. 2011;133:14755–64.CrossRefGoogle Scholar
  65. 65.
    Clore GM, Gronenborn AM, Mitchinson C, Green NM. 1H-NMR studies on nucleotide binding to the sarcoplasmic reticulum Ca2+ ATPase. Determination of the conformations of bound nucleotides by the measurement of proton-proton transferred nuclear Overhauser enhancements. Eur J Biochem. 1982;128:113–7.CrossRefGoogle Scholar
  66. 66.
    Ueda T, Takeuchi K, Nishida N, Stampoulis P, Kofuku Y, Osawa M, Shimada I. Cross-saturation and transferred cross-saturation experiments. Q Rev Biophys. 2014;47:143–87.CrossRefGoogle Scholar
  67. 67.
    Takahashi H, Nakanishi T, Kami K, Arata Y, Shimada I. A novel NMR method for determining the interfaces of large protein-protein complexes. Nat Struct Biol. 2000;7:220–3.CrossRefGoogle Scholar
  68. 68.
    Nakanishi T, Miyazawa M, Sakakura M, Terasawa H, Takahashi H, Shimada I. Determination of the interface of a large protein complex by transferred cross-saturation measurements. J Mol Biol. 2002;318:245–9.CrossRefGoogle Scholar
  69. 69.
    Nishida N, Sumikawa H, Sakakura M, Shimba N, Takahashi H, Terasawa H, Suzuki EI, Shimada I. Collagen-binding mode of vWF-A3 domain determined by a transferred cross-saturation experiment. Nat Struct Biol. 2003;10:53–8.CrossRefGoogle Scholar
  70. 70.
    Dosset P, Hus JC, Marion D, Blackledge M. A novel interactive tool for rigid-body modeling of multi-domain macromolecules using residual dipolar couplings. J Biomol NMR. 2001;20:223–31.CrossRefGoogle Scholar
  71. 71.
    McCoy MA, Wyss DF. Structures of protein-protein complexes are docked using only NMR restraints from residual dipolar coupling and chemical shift perturbations. J Am Chem Soc. 2002;124:2104–5.CrossRefGoogle Scholar
  72. 72.
    Tycko R, Blanco FJ, Ishii Y. Alignment of biopolymers in strained gels: a new way to create detectable dipole-dipole couplings in high-resolution biomolecular NMR. J Am Chem Soc. 2000;122:9340–1.CrossRefGoogle Scholar
  73. 73.
    Hansen MR, Hanson P, Pardi A. Filamentous bacteriophage for aligning RNA, DNA, and proteins for measurement of nuclear magnetic resonance dipolar coupling interactions. RNA-Ligand Interact A. 2000;317:220–40.CrossRefGoogle Scholar
  74. 74.
    Tjandra N, Bax A. Direct measurement of distances and angles in biomolecules by NMR in a dilute liquid crystalline medium. Science. 1997;278:1697.CrossRefGoogle Scholar
  75. 75.
    Lorieau J, Yao LS, Bax A. Liquid crystalline phase of G-tetrad DNA for NMR study of detergent-solubilized proteins. J Am Chem Soc. 2008;130:7536.CrossRefGoogle Scholar
  76. 76.
    Xu X, Keizers PH, Reinle W, Hannemann F, Bernhardt R, Ubbink M. Intermolecular dynamics studied by paramagnetic tagging. J Biomol NMR. 2009;43:247–54.CrossRefGoogle Scholar
  77. 77.
    Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM. Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation. J Mol Biol. 2001;312:481–99.CrossRefGoogle Scholar
  78. 78.
    Zweckstetter M, Bax A. Evaluation of uncertainty in alignment tensors obtained from dipolar couplings. J Biomol NMR. 2002;23:127–37.CrossRefGoogle Scholar
  79. 79.
    Blackledge M. Recent progress in the study of biomolecular structure and dynamics in solution from residual dipolar couplings. Prog Nucl Magn Reson Spectrosc. 2005;46:23–61.CrossRefGoogle Scholar
  80. 80.
    Simon B, Madl T, Mackereth CD, Nilges M, Sattler M. An efficient protocol for NMR-spectroscopy-based structure determination of protein complexes in solution. Angew Chem Int Ed. 2010;49:1967–70.CrossRefGoogle Scholar
  81. 81.
    Ortega-Roldan JL, Jensen MR, Brutscher B, Azuaga AI, Blackledge M, van Nuland NA. Accurate characterization of weak macromolecular interactions by titration of NMR residual dipolar couplings: application to the CD2AP SH3-C:ubiquitin complex. Nucleic Acids Res. 2009;37:e70.CrossRefGoogle Scholar
  82. 82.
    Tolman JR, Ruan K. NMR residual dipolar couplings as probes of biomolecular dynamics. Chem Rev. 2006;106:1720–36.CrossRefGoogle Scholar
  83. 83.
    Clore GM. Practical aspects of paramagnetic relaxation enhancement in biological macromolecules. Methods Enzymol. 2015;564:485–97.CrossRefGoogle Scholar
  84. 84.
    Nitsche C, Otting G. Pseudocontact shifts in biomolecular NMR using paramagnetic metal tags. Prog Nucl Magn Reson Spectrosc. 2017;98-99:20–49.CrossRefGoogle Scholar
  85. 85.
    Hocking HG, Zangger K, Madl T. Studying the structure and dynamics of biomolecules by using soluble paramagnetic probes. Chemphyschem. 2013;14:3082–94.CrossRefGoogle Scholar
  86. 86.
    Battiste JL, Wagner G. Utilization of site-directed spin labeling and high-resolution heteronuclear nuclear magnetic resonance for global fold determination of large proteins with limited nuclear overhauser effect data. Biochemistry. 2000;39:5355–65.CrossRefGoogle Scholar
  87. 87.
    Clore GM, Iwahara J. Theory, practice, and applications of paramagnetic relaxation enhancement for the characterization of transient low-population states of biological macromolecules and their complexes. Chem Rev. 2009;109:4108–39.CrossRefGoogle Scholar
  88. 88.
    Pintacuda G, Park AY, Keniry MA, Dixon NE, Otting G. Lanthanide labeling offers fast NMR approach to 3D structure determinations of protein-protein complexes. J Am Chem Soc. 2006;128:3696–702.CrossRefGoogle Scholar
  89. 89.
    Saio T, Yokochi M, Kumeta H, Inagaki F. PCS-based structure determination of protein-protein complexes. J Biomol NMR. 2010;46:271–80.CrossRefGoogle Scholar
  90. 90.
    Schmitz C, John M, Park AY, Dixon NE, Otting G, Pintacuda G, Huber T. Efficient chi-tensor determination and NH assignment of paramagnetic proteins. J Biomol NMR. 2006;35:79–87.CrossRefGoogle Scholar
  91. 91.
    Jeschke G. Conformational dynamics and distribution of nitroxide spin labels. Prog Nucl Magn Reson Spectrosc. 2013;72:42–60.CrossRefGoogle Scholar
  92. 92.
    John M, Otting G. Strategies for measurements of pseudocontact shifts in protein NMR spectroscopy. Chemphyschem. 2007;8:2309–13.CrossRefGoogle Scholar
  93. 93.
    Keizers PHJ, Saragliadis A, Hiruma Y, Overhand M, Ubbink M. Design, synthesis, and evaluation of a lanthanide chelating protein probe: CLaNP-5 yields predictable paramagnetic effects independent of environment. J Am Chem Soc. 2008;130:14802–12.CrossRefGoogle Scholar
  94. 94.
    Liu WM, Keizers PHJ, Hass MAS, Blok A, Tirnmer M, Sarris AJC, Overhand M, Ubbink M. A pH-sensitive, colorful, lanthanide-chelating paramagnetic NMR probe. J Am Chem Soc. 2012;134:17306–13.CrossRefGoogle Scholar
  95. 95.
    Ubbink M, Ejdeback M, Karlsson BG, Bendall DS. The structure of the complex of plastocyanin and cytochrome f, determined by paramagnetic NMR and restrained rigid-body molecular dynamics. Structure. 1998;6:323–35.CrossRefGoogle Scholar
  96. 96.
    Keizers PHJ, Mersinli B, Reinle W, Donauer J, Hiruma Y, Hannemann F, Overhand M, Bernhardt R, Ubbink M. A Solution model of the complex formed by adrenodoxin and adrenodoxin reductase determined by paramagnetic NMR spectroscopy. Biochemistry. 2010;49:6846–55.CrossRefGoogle Scholar
  97. 97.
    Miao YM, Cross TA. Solid state NMR and protein-protein interactions in membranes. Curr Opin Struct Biol. 2013;23:919–28.CrossRefGoogle Scholar
  98. 98.
    Tang M, Comellas G, Rienstra CM. Advanced solid-state NMR approaches for structure determination of membrane proteins and amyloid fibrils. Acc Chem Res. 2013;46:2080–8.CrossRefGoogle Scholar
  99. 99.
    Kozlova AS, Cross TA, Brey WW, Gor’kov PL. P-31 and N-15 solid-state NMR study for the development of a novel membrane protein drug-screening methodology. Biophys J. 2012;102:390a.CrossRefGoogle Scholar
  100. 100.
    Zhou HX, Cross TA. Influences of membrane mimetic environments on membrane protein structures. Annu Rev Biophys. 2013;42:361–92.CrossRefGoogle Scholar
  101. 101.
    Bhate MP, Wylie BJ, Tian L, McDermott AE. Conformational dynamics in the selectivity filter of KcsA in response to potassium ion concentration. J Mol Biol. 2010;401:155–66.CrossRefGoogle Scholar
  102. 102.
    Pandit A, Reus M, Morosinotto T, Bassi R, Holzwarth AR, de Groot HJM. An NMR comparison of the light-harvesting complex II (LHCII) in active and photoprotective states reveals subtle changes in the chlorophyll a ground-state electronic structures. BBA-Bioenergetics. 1827;2013:738–44.Google Scholar
  103. 103.
    Tang M, Sperling LJ, Berthold DA, Schwieters CD, Nesbitt AE, Nieuwkoop AJ, Gennis RB, Rienstra CM. High-resolution membrane protein structure by joint calculations with solid-state NMR and X-ray experimental data. J Biomol NMR. 2011;51:227–33.CrossRefGoogle Scholar
  104. 104.
    Meier BH, Bockmann A. The structure of fibrils from “misfolded” proteins. Curr Opin Struct Biol. 2015;30:43–9.CrossRefGoogle Scholar
  105. 105.
    Bolshette NB, Thakur KK, Bidkar AP, Trandafir C, Kumar P, Gogoi R. Protein folding and misfolding in the neurodegenerative disorders: a review. Rev Neurol (Paris). 2014;170:151–61.CrossRefGoogle Scholar
  106. 106.
    Tycko R. Amyloid polymorphism: structural basis and neurobiological relevance. Neuron. 2015;86:632–45.CrossRefGoogle Scholar
  107. 107.
    Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R. Molecular structure of beta-amyloid fibrils in Alzheimer’s disease brain tissue. Cell. 2013;154:1257–68.CrossRefGoogle Scholar
  108. 108.
    Habenstein B, Bousset L, Sourigues Y, Kabani M, Loquet A, Meier BH, Melki R, Bockmann A. A native-like conformation for the C-terminal domain of the prion Ure2p within its fibrillar form. Angew Chem Int Ed Engl. 2012;51:7963–6.CrossRefGoogle Scholar
  109. 109.
    van der Wel PC, Lewandowski JR, Griffin RG. Solid-state NMR study of amyloid nanocrystals and fibrils formed by the peptide GNNQQNY from yeast prion protein Sup35p. J Am Chem Soc. 2007;129:5117–30.CrossRefGoogle Scholar
  110. 110.
    Gath J, Bousset L, Habenstein B, Melki R, Bockmann A, Meier BH. Unlike twins: an NMR comparison of two alpha-synuclein polymorphs featuring different toxicity. PLoS One. 2014;9, e90659.CrossRefGoogle Scholar
  111. 111.
    Palmer 3rd AG, Kroenke CD, Loria JP. Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules. Methods Enzymol. 2001;339:204–38.CrossRefGoogle Scholar
  112. 112.
    Anthis NJ, Clore GM. Visualizing transient dark states by NMR spectroscopy. Q Rev Biophys. 2015;48:35–116.CrossRefGoogle Scholar
  113. 113.
    Vallurupalli P, Hansen DF, Kay LE. Structures of invisible, excited protein states by relaxation dispersion NMR spectroscopy. Proc Natl Acad Sci U S A. 2008;105:11766–71.CrossRefGoogle Scholar
  114. 114.
    Fawzi NL, Ying J, Ghirlando R, Torchia DA, Clore GM. Atomic-resolution dynamics on the surface of amyloid-beta protofibrils probed by solution NMR. Nature. 2011;480:268–72.CrossRefGoogle Scholar
  115. 115.
    Fawzi NL, Ying J, Torchia DA, Clore GM. Kinetics of amyloid beta monomer-to-oligomer exchange by NMR relaxation. J Am Chem Soc. 2010;132:9948–51.CrossRefGoogle Scholar
  116. 116.
    Libich DS, Tugarinov V, Clore GM. Intrinsic unfoldase/foldase activity of the chaperonin GroEL directly demonstrated using multinuclear relaxation-based NMR. Proc Natl Acad Sci U S A. 2015;112:8817–23.CrossRefGoogle Scholar
  117. 117.
    Libich DS, Tugarinov V, Ghirlando R, Clore GM. Confinement and stabilization of Fyn SH3 folding intermediate mimetics within the cavity of the chaperonin GroEL demonstrated by relaxation-based NMR. Biochemistry. 2017;56:903–6.CrossRefGoogle Scholar
  118. 118.
    Arnold K, Bordoli L, Kopp J, Schwede T. The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics. 2006;22:195–201.CrossRefGoogle Scholar
  119. 119.
    Pieper U, Webb BM, Dong GQ, Schneidman-Duhovny D, Fan H, Kim SJ, Khuri N, Spill YG, Weinkam P, Hammel M, et al. ModBase, a database of annotated comparative protein structure models and associated resources. Nucleic Acids Res. 2014;42:D336–46.CrossRefGoogle Scholar
  120. 120.
    Shen Y, Vernon R, Baker D, Bax A. De novo protein structure generation from incomplete chemical shift assignments. J Biomol NMR. 2009;43:63–78.CrossRefGoogle Scholar
  121. 121.
    Wishart DS, Arndt D, Berjanskii M, Tang P, Zhou J, Lin G. CS23D: a web server for rapid protein structure generation using NMR chemical shifts and sequence data. Nucleic Acids Res. 2008;36:W496–502.CrossRefGoogle Scholar
  122. 122.
    Madl T, Gabel F, Sattler M. NMR and small-angle scattering-based structural analysis of protein complexes in solution. J Struct Biol. 2011;173:472–82.CrossRefGoogle Scholar
  123. 123.
    Schwieters CD, Suh JY, Grishaev A, Ghirlando R, Takayama Y, Clore GM. Solution structure of the 128 kDa enzyme I dimer from Escherichia coli and its 146 kDa complex with HPr using residual dipolar couplings and small- and wide-angle X-ray scattering. J Am Chem Soc. 2010;132:13026–45.CrossRefGoogle Scholar
  124. 124.
    Hennig J, Sattler M. The dynamic duo: combining NMR and small angle scattering in structural biology. Protein Sci. 2014;23:669–82.CrossRefGoogle Scholar
  125. 125.
    Rossi P, Shi L, Liu GH, Barbieri CM, Lee HW, Grant TD, Luft JR, Xiao R, Acton TB, Snell EH, et al. A hybrid NMR/SAXS-based approach for discriminating oligomeric protein interfaces using Rosetta. Proteins Struct Funct Bioinf. 2015;83:309–17.CrossRefGoogle Scholar
  126. 126.
    Banham JE, Timmel CR, Abbott RJ, Lea SM, Jeschke G. The characterization of weak protein-protein interactions: evidence from DEER for the trimerization of a von Willebrand factor A domain in solution. Angew Chem Int Ed Engl. 2006;45:1058–61.CrossRefGoogle Scholar
  127. 127.
    Zhang Y, Hu Y, Li H, Jin C. Structural basis for TatA oligomerization: an NMR study of Escherichia coli TatA dimeric structure. PLoS One. 2014;9:e103157.CrossRefGoogle Scholar
  128. 128.
    Byeon IJL, Meng X, Jung JW, Zhao GP, Yang RF, Ahn JW, Shi J, Concel J, Aiken C, Zhang PJ, et al. Structural convergence between cryo-EM and NMR reveals intersubunit interactions critical for HIV-1 capsid function. Cell. 2009;139:780–90.CrossRefGoogle Scholar
  129. 129.
    Berry JL, Phelan MM, Collins RF, Adomavicius T, Tonjum T, Frye SA, Bird L, Owens R, Ford RC, Lian LY, et al. Structure and assembly of a trans-periplasmic channel for type IV Pili in Neisseria meningitidis. PLoS Pathog. 2012;8:e1002923.CrossRefGoogle Scholar
  130. 130.
    Musselman CA, Gibson MD, Hartwick EW, North JA, Gatchalian J, Poirier MG, Kutateladze TG. Binding of PHF1 Tudor to H3K36me3 enhances nucleosome accessibility. Nat Commun. 2013;4:2969.CrossRefGoogle Scholar
  131. 131.
    Walzthoeni T, Leitner A, Stengel F, Aebersold R. Mass spectrometry supported determination of protein complex structure. Curr Opin Struct Biol. 2013;23:252–60.CrossRefGoogle Scholar
  132. 132.
    Rutsdottir G, Harmark J, Weide Y, Hebert H, Rasmussen MI, Wernersson S, Respondek M, Akke M, Hojrup P, Koeck PJ, et al. Structural model of dodecameric heat-shock protein Hsp21 – flexible N-terminal arms interact with client proteins while C-terminal tails maintain the dodecamer and chaperone activity. J Biol Chem. 2017.
  133. 133.
    Prischi F, Pastore A. Hybrid methods in iron-sulfur cluster biogenesis. Front Mol Biosci. 2017;4:12.CrossRefGoogle Scholar
  134. 134.
    Huang C, Kalodimos CG. Structures of large protein complexes determined by nuclear magnetic resonance spectroscopy. Annu Rev Biophys. 2017.
  135. 135.
    Karagoz GE, Duarte AM, Akoury E, Ippel H, Biernat J, Moran Luengo T, Radli M, Didenko T, Nordhues BA, Veprintsev DB, et al. Hsp90-Tau complex reveals molecular basis for specificity in chaperone action. Cell. 2014;156:963–74.CrossRefGoogle Scholar
  136. 136.
    Sattler M, Fesik SW. Use of deuterium labeling in NMR: overcoming a sizeable problem. Structure. 1996;4:1245–9.CrossRefGoogle Scholar
  137. 137.
    Bezsonova I, Bruce MC, Wiesner S, Lin H, Rotin D, Forman-Kay JD. Interactions between the three CIN85 SH3 domains and ubiquitin: implications for CIN85 ubiquitination. Biochemistry. 2008;47:8937–49.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of MedicineUniversity of TasmaniaHobartAustralia
  2. 2.School of Life and Environmental SciencesUniversity of SydneySydneyAustralia

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