Visualization of transient encounter complexes in protein–protein association
Abstract
Kinetic data on a number of protein-protein associations have provided evidence for the initial formation of a pre-equilibrium encounter complex that subsequently relaxes to the final stereospecific complex. Site-directed mutagenesis and brownian dynamics simulations have suggested that the rate of association can be modulated by perturbations in charge distribution outside the direct interaction surfaces. Furthermore, rate enhancement through non-specific binding may occur by either a reduction in dimensionality or the presence of a short-range, non-specific attractive potential. Here, using paramagnetic relaxation enhancement, we directly demonstrate the existence and visualize the distribution of an ensemble of transient, non-specific encounter complexes under equilibrium conditions for a relatively weak protein-protein complex between the amino-terminal domain of enzyme I and the phosphocarrier protein HPr. Neither the stereospecific complex alone nor any single alternative conformation can account fully for the intermolecular paramagnetic relaxation enhancement data. Restrained rigid-body simulated annealing refinement against the paramagnetic relaxation enhancement data enables us to obtain an atomic probability distribution map of the non-specific encounter complex ensemble that qualitatively correlates with the electrostatic surface potentials on the interacting proteins. Qualitatively similar results are presented for two other protein-protein complexes.
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The broad spatial distribution of PRE effects likely reflects dynamic binding with multiple low-affinity interactions.
“In all cases, the broad spatial distribution of PRE effects likely reflects the dynamic binding with multiple low-affinity interactions that are reflected by the paramagnetic effects (52).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [52]
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Huang, J., Warner, L., Sanchez, C., Gabel, F., Madl, T., Mackereth, C. D., Sattler, M., & Blackledge, M. J. (2014) · Journal of the American Chemical Society · doi:10.1021/ja502030n · Cited by 76 · see citing works
Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane
Fang, Z., Lee, K., Huo, K.-G., Gasmi-Seabrook, G. M. C., Zheng, L., Moghal, N., Tsao, M., Ikura, M., & Marshall, C. B. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1914076117 · Cited by 74 · see citing works
Chen, J., Dima, R. I., & Thirumalai, D. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.08.047 · Cited by 74 · see citing works
Examination of Matrix Metalloproteinase-1 in Solution
Cerofolini, L., Fields, G. B., Fragai, M., Geraldes, C. F. G. C., Luchinat, C., Parigi, G., Ravera, E., Svergun, D. I., & Teixeira, J. M. C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.477240 · Cited by 73 · see citing works
Grishaev, A., Ying, J., Canny, M. D., Pardi, A., & Bax, A. (2008) · Journal of Biomolecular NMR · doi:10.1007/s10858-008-9267-x · Cited by 73 · see citing works
Exploring sparsely populated states of macromolecules by diamagnetic and paramagnetic NMR relaxation
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Self-citationToward an Accurate Determination of Free Energy Landscapes in Solution States of Proteins
Simone, A. D., Richter, B., Salvatella, X., & Vendruscolo, M. (2009) · Journal of the American Chemical Society · doi:10.1021/ja8087295 · Cited by 70 · see citing works
Clore, G. M., & Venditti, V. (2013) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.08.003 · Cited by 69 · see citing works
Self-citationClore, G. M. (2008) · Molecular BioSystems · doi:10.1039/b810232e · Cited by 69 · see citing works
Self-citationFormation of transient protein complexes
Schilder, J. T., & Ubbink, M. (2013) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2013.07.009 · Cited by 68 · see citing works
Intrinsically disordered proteins may escape unwanted interactions via functional misfolding
Uversky, V. N. (2011) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2011.03.010 · Cited by 65 · see citing works
Probing protein surface accessibility with solvent and paramagnetic molecules
Bernini, A., Venditti, V., Spiga, O., & Niccolai, N. (2008) · Progress in Nuclear Magnetic Resonance Spectroscopy · doi:10.1016/j.pnmrs.2008.10.003 · Cited by 64 · see citing works
Transient Weak Protein–Protein Complexes Transfer Heme Across the Cell Wall of Staphylococcus aureus
Villareal, V. A., Spirig, T., Robson, S. A., Liu, M., Lei, B., & Clubb, R. (2011) · Journal of the American Chemical Society · doi:10.1021/ja203805b · Cited by 63 · see citing works
Antal, M., Böde, C., & Csermely, P. (2009) · Current Protein and Peptide Science · doi:10.2174/138920309787847617 · Cited by 62 · see citing works
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A rigid disulfide-linked nitroxide side chain simplifies the quantitative analysis of PRE data
Fawzi, N. L., Fleissner, M. R., Anthis, N. J., Kálai, T., Hideg, K., Hubbell, W. L., & Clore, G. M. (2011) · Journal of Biomolecular NMR · doi:10.1007/s10858-011-9545-x · Cited by 61 · see citing works
Self-citationMembrane interactions of intrinsically disordered proteins: The example of alpha-synuclein
Das, T., & Eliezer, D. (2019) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2019.05.001 · Cited by 61 · see citing works
- Authors
- Tang, C., Iwahara, J., & Clore, G. M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Clore, G. Marius
- Venue
- Nature
- Published
- 2006-10-15
- Volume
- 444
- Issue
- 7117
- Pages
- 383-386
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2063810968
- Cited by
- 406
- References
- 26
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 14 · 2021: 10 · 2020: 16 · 2019: 19 · 2018: 15 · 2017: 15 · 2016: 23 · 2015: 28 · 2014: 22 · 2013: 32 · 2012: 30
- FWCI
- 12.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Keywords
- protein-protein interaction, non-specific binding, paramagnetic relaxation enhancement, surface electrostatic potential
- MeSH terms
- Bacterial Proteins, Enzymes, Kinetics, Models, Molecular, Phosphoenolpyruvate Sugar Phosphotransferase System, Protein Binding, Protein Conformation, Nuclear Magnetic Resonance, Biomolecular, Multiprotein Complexes, Static Electricity
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