Skip to main content
SpringerLink
Log in

T-R Transition

  • Chapter
Insulin & Related Proteins - Structure to Function and Pharmacology

  • 388 Accesses

Abstract

Insulin hexamers crystallize in essentially three different structural states that have all been defined by high-resolution X-ray analysis. In solution these structural states are related by dynamic equilibria, the transitions between them being ligand controlled. The history of the detection and investigation of the solution structural transitions is outlined and a few recent results are presented. Meanwhile insulin has been established as an outstanding model for the study of allosterism and cooperativity, respectively.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Adams M.J., Blundell T.L., Dodson E.J., Dodson G.G., Vijayan M., Baker E.N., Harding M.M., Hodgkin D.C., Rimmer B. and Sheat S. Nature 224 (1969): 491–---

    CAS  Google Scholar 

  • Bentley G.A., Brange J., Derewenda Z., Dodson E.J., Dodson G.G., Wilkinson A.J., Wollmer A. and Xiao B. “Role of B13 Glu in Insulin Assembly. The hexamer Structure of Recombinant Mutant [B13 Glu → Gln]insulin.” J. Mol. Biol. 228 (1992): 1163–1176.

    Article  PubMed  CAS  Google Scholar 

  • Bentley G.A., Dodson G.G., Dodson E.J., Hodgkin D.C. and Mercola D.A. “Structure of insulin in 4-zinc insulin.” Nature 261 (1976): 166–168 (1976)

    Article  PubMed  CAS  Google Scholar 

  • Bentley G.A., Dodson G.G., Dodson E.J., Hodgkin D.C., Mercola D.A. and Wollmer A. “Structural Rearrangement in Insulin; a Comparison of 2 and 4 Zinc Insulin Structures.” Paper presented at the Spring Meeting of the British Diabetic Association, (1975), Sheffield, UK.

    Google Scholar 

  • Bentley G., Dodson G. and Lewitova A. “Rhombohedral Insulin Crystal Transformation.” J. Mol. Biol. 126 (1978): 871–875.

    Article  PubMed  CAS  Google Scholar 

  • Berchtold H. and Hilgenfeld R. “Binding of Phenol to R 6 Insulin Hexamers.” Inc. Biopoly 51 (1999): 165–172.

    CAS  Google Scholar 

  • Bimbaum D.T., Kilcomons M.A., DeFelippis M.R. and Beals J.M. “Assembly and Dissociation of Human Insulin and LysB28ProB29-Insulin Hexamers: A Comparison Study.” Pharmaceutical Research 14 (1997): 25–36.

    Google Scholar 

  • Bloom C.R., Choi W.E., Brzovic P.S., Ha J.J., Huang S.-T., Kaarsholm N.C. and Dunn M.F. “Ligand Binding to Wild-type and E-B13Q Mutant Insulins: A Three-state Allosteric Model System Showing Half-site Reactivity.”J. Mol. Biol. 245 (1995): 324–330.

    Article  PubMed  CAS  Google Scholar 

  • Bloom C.R., Heymann R., Kaarsholm N.C. and Dunn M.F. “Binding of 2,6-and 2,7-Dihydroxynaphthalene to Wild-Type and E-B13Q Insulins: Dynamic, Equilibrium, and Molecular Modeling Investigations. Biochemistry 36 (1997): 12746–12758.

    PubMed  CAS  Google Scholar 

  • Bloom C.R., Kaarsholm N.C., Ha J. and Dunn M.F. “Half-Site Reactivity, Negative Cooperativity, and Positive Cooperativity: Quantitative Considerations of a Plausible Model.” Biochemistry 36 (1997): 12759–12765.

    PubMed  CAS  Google Scholar 

  • Bloom C.R., Wu N., Dunn, A., Kaarsholm, N.C. and Dunn, M.F. “Comparison of the Allosteric Properties of the Co(II)-and Zn(II)-Substituted Insulin Hexamers.” Biochemistry 37 (1998): 10937–10944.

    Article  PubMed  CAS  Google Scholar 

  • Brader M.L. and Dunn M.F. “Insulin hexamers: new conformations and applications.” TIBS 16 (1991): 341–345.

    PubMed  CAS  Google Scholar 

  • Brader M.L., Kaarsholm N.C., Lee R.W.-K. and Dunn M.F. “Characterization of the R-State Insulin Hexamer and Its Derivatives. The Hexamer Is Stabilized by Heterotropic Ligand Binding Interactions.” Biochemistry 30 (1991): 6636–6645.

    Article  PubMed  CAS  Google Scholar 

  • Brzovic P.S., Choi W.E., Borchardt D., Kaarsholm N.C. and Dunn M.F. “Structural Asymmetry and Half-Site Reactivity in the T to R Allosteric Transition of the Insulin Hexamer.” Biochemistry 33 (1994): 13057–13069.

    Article  PubMed  CAS  Google Scholar 

  • Choi W.E., Brader M.L., Aguilar V., Kaarsholm N.C. and Dunn M.F. “The Allosteric Transition of the Insulin Hexamer Is Modulated by Homotropic and Heterotropic Interactions.” Biochemistry 32 (1993): 11638–11645.

    PubMed  CAS  Google Scholar 

  • Choi W.E., Borchardt D., Kaarsholm N.C., Brzovic P.S. and Dunn M.F. “Spectroscopic Evidence for Preexisting T-and R-State Insulin Hexamer Conformations.” Proteins: Structure, Function, and Genetics 26 (1996): 377–390.

    Article  CAS  Google Scholar 

  • Chothia C., Lesk A.M., Dodson G.G. and Hodgkin D.C. “Transmission of conformational change in insulin.” Nature 302 (1983): 500–505.

    Article  PubMed  CAS  Google Scholar 

  • Ciszak E. and Smith G.D. “Crystallographic Evidence for Dual Coordination areound Zinc in the Human Insulin Hexamer.” Biochemistry 33 (1994): 1512–1517.

    Article  PubMed  CAS  Google Scholar 

  • Derewenda U., Derewenda Z., Dodson E.J., Dodson G.G., Reynolds C.D., Smith G.D., Sparks C. and Swenson D. “Phenol stabilizes more helix in a new symmetrical zinc insulin hexamer.” Nature 338 (1989): 594–596.

    Article  PubMed  CAS  Google Scholar 

  • Derewenda U., Derewenda Z., Dodson G.G., Hubbard R.E. and Korber F. “Molecular structure of insulin: The insulin monomer and its assembly.” British Medical Bulletin 45 (1989): 4–18.

    PubMed  CAS  Google Scholar 

  • Derewenda U., Derewenda Z.S., Dodson G.G. and Hubbard R.E. “Insulin Structure.” In: Handbook of Experimental Pharmacology, Vol 92 (P. Cuatrecasas and S. Jacobs, eds.), (1990) Springer Verlag, Berlin, pp. 23–39.

    Google Scholar 

  • Dodson E.J., Dodson G.G., Hubbard R.E. and Reynolds C.D. “Insulin’s Structural Behavior and Its Relation to Activity.” Biopolymers 22 (1983): 281–291.

    Article  PubMed  CAS  Google Scholar 

  • Engels M., Jacoby E., Krüger P., Schlitter J. and Wollmer A. “TheT↔R structural transition of Insulin; pathways suggested by targeted energy minimization.” Protein Engineering 5 (1992): 669–677.

    PubMed  CAS  Google Scholar 

  • Fabris D. and Fenselau C. “Characterization of Allosteric Insulin Hexamers by Electrospray lonization Mass Spectrometry.” Anal Chem. 71 (1999): 384–387.

    Article  PubMed  CAS  Google Scholar 

  • Gross L. and Dunn M.F. “Spectroscopic Evidence for an Intermediate in the T6 to R6 Allosteric Transition of the Co(II)-Substituted Insulin Hexamer.” Biochemistry 31 (1992): 1295–1301.

    Article  PubMed  CAS  Google Scholar 

  • Hardaway L.A., Brems D.N., Beals J.M. and MacKenzie N.E. “Amide hydrogen exchange of the central B-chain helix within the T-and R-states of insulin hexamers.” Biochim. Biophys. Ada 1208 (1994): 101–103.

    CAS  Google Scholar 

  • Huang S.T., Choi W.E., Bloom C., Leuenberger M. and Dunn M.F. “Carboxylate Ions Are Strong Allosteric Ligands for the HisB10 Sites of the R-State Insulin Hexamer.” Biochemistry 36 (1997): 9878–9888.

    PubMed  CAS  Google Scholar 

  • Jacoby E., Krüger P., Karatas Y. and Wollmer A. “Distinction of Structural Reorganisation and Ligand Binding in the Transition of Insulin on the Basis of Allosteric Models.” Biol. Chem. Hoppe-Seyler 374 (1993): 877–885.

    PubMed  CAS  Google Scholar 

  • Kaarsholm N.C., Ko H.-C. and Dunn M.F. Biochemistry 28 (1989): 4427–4435.

    Article  PubMed  CAS  Google Scholar 

  • Kadima W. Biochemistry 38 (1999): 13443–13452.

    Article  PubMed  CAS  Google Scholar 

  • Kadima W., Roy M., Lee R. W.-K., Kaarsholm N.C. and Dunn M.F. “Studies of the Association and Conformational Properties of Metal-free Insulin in Alkaline Sodium Chloride Solutions by One-and Two-dimensional 1H NMR.” J. Biol. Chem. 267 (1992): 8963–8970.

    PubMed  CAS  Google Scholar 

  • Karatas Y., Krüger P. and Wollmer A. “Kinetic Measurements of T↔R Structural Transitions in Insulin.” Biol. Chem. Hoppe-Seyler 372 (1991): 1035–1038.

    PubMed  CAS  Google Scholar 

  • Kim Y. and Shields J.E. “pH Dependent Conformational Changes in the T-and R-States of Insulin in Solution: Circular Dichroic Studies in the pH Range of 6 to 10.” Biochem. Biophys. Res. Commun. 186 (1992): 1115–1120.

    PubMed  CAS  Google Scholar 

  • Krüger P., Gilge G., Cabuk Y. and Wollmer A. “Cooperativity and Intermediate States in the T↔R-Structural Transformation of Insulin.” Biol. Chem. Hoppe-Seyler 371 (1990): 669–673.

    PubMed  Google Scholar 

  • Markussen J., Andersen A.S., Kaarsholm N.C., Kjeldsen T., Olsen O.H. and Schaffer L. “Insulin and Its Receptor.” In: Frontiers in Insulin Pharmacology (M. Berger and F.A. Gries, eds.), (1993) Georg Thieme Verlag, Stuttgart, pp. 1–16.

    Google Scholar 

  • Nakagawa S.H. and Tager H.S. “Implications of Invariant Residue LeuB6 in Insulin-Receptor Interactions.” J. Biol. Chem. 266 (1991): 11502–11509.

    PubMed  CAS  Google Scholar 

  • O’Donoghue S.I., Chang X., Abseher R., Nilges M. and Led J.J. “Unraveling the symmetry ambiguity in a hexamer: Calculation of the R 6 human insulin structure.” J. Biomol. NMR 16 (2000): 93–108.

    Google Scholar 

  • Pittman I. and Tager H.S. “A Spectroscopic Investigation of the Conformational Dynamics of Insulin in Solution.” Biochemistry 34 (1995): 10578–10590.

    Article  PubMed  CAS  Google Scholar 

  • Rahuel-Clermont S., French C.A., Kaarsholm N.C. and Dunn M.F. “Mechanisms of Stabilization of the Insulin Hexamer through Allosteric Ligand Interactions.” Biochemistry 36 (1997): 5837–5845.

    Article  PubMed  CAS  Google Scholar 

  • Ramesh V. and Bradbury J.H. “H n.m.r. studies of insulin.” Int. J. Peptide Protein Res. 28 (1986): 146–153.

    CAS  Google Scholar 

  • Renscheidt H. (1982) Diploma Dissertation, RWTH Aachen.

    Google Scholar 

  • Renscheidt H., Straβburger W., Glatter U., Wollmer A., Dodson G.G. and Mercola D.A. “A solution equivalent of the 2Zn→4Zn transformation of insulin in the crystal.” Eur. J. Biochem. 142 (1984): 7–14.

    Article  PubMed  CAS  Google Scholar 

  • Roy M., Brader M.L., Lee R.W.-K., Kaarsholm N.C., Hansen J.F. and Dunn M.F. “Spectroscopic Signatures of the T to R Conformational Transition in the Insulin Hexamer.” J. Biol. Chem. 264 (1989): 19081–19085.

    PubMed  CAS  Google Scholar 

  • Schlichtkrull J. (1958) Dissertation, University of Copenhagen, Munskgaard

    Google Scholar 

  • Schlitter J., Engels M., Krüger P. Jacoby E. and Wollmer A. “Targeted Molecular Dynamics Simulation of Conformational Change —Application to the T↔R Transition in Insulin.” Molecular Simulation 10 (1993): 291–308.

    CAS  Google Scholar 

  • Shneine J., Voswinkel M., Federwisch M. and Wollmer A. “Enhancing the T↔R Transition of Insulin by Helix-Promoting Sequence Modifications at the N-Terminal B-Chain.” Biol. Chem. 381 (2000): 127–133.

    Article  PubMed  CAS  Google Scholar 

  • Smith G.D. “The phenolic binding site in T 3 R 3 f insulin1” J. Molecular Structure 469 (1998): 71–80.

    Google Scholar 

  • Smith G.D. and Ciszak E. “The structure of a complex of hexameric insulin and 4’-hydroxyacetanilide.” Proc. Natl. Acad. Sci. USA 91 (1994): 8851–8855.

    PubMed  CAS  Google Scholar 

  • Smith G.D. and Dodson G.G. “The Structure of a Rhombohedral R 6 Insulin Hexamer That Binds Phenol.” Biopolymers 32 (1992): 441–445.

    PubMed  CAS  Google Scholar 

  • Smith G.D., Ciszak E. and Pangborn W. “A novel complex of a phenolic derivative with insulin: Structural features related to the T→R transition.” Protein Science 5 (1996): 1502–1511.

    PubMed  CAS  Google Scholar 

  • Smith G.D., Swenson D.C., Dodson E.J., Dodson G.G. and Reynolds C.D. “Structural stability in the 4-zinc human insulin hexamer.” Proc. Natl. Acad. Sci. USA 81 (1984): 7093–7097.

    PubMed  CAS  Google Scholar 

  • Smith G.D., Ciszak E. Magrum L.A., Pangborn W.A. and Blessing R.H. “ R 6 hexameric insulin complexed with m-cresol or resorcinol.” Ada Cryst. D56 (2000): 1541–1548.

    CAS  Google Scholar 

  • Storm M.C. and Dunn M.F. “The Glu(B13) Carboxylates of the Insulin Hexamer Form a Cage for Cd2+ and Ca2+ Ions.” Biochemistry 24 (1985): 1749–1756.

    Article  PubMed  CAS  Google Scholar 

  • Tang L., Whittingham J.L., Verma C.S., Caves L.S.D. and Dodson G.G. “Structural Consequences of the B5 Histidine → Tyrosine Mutation in Human Insulin Characterized by X-Ray Crystallography and Conformational Analysis.” Biochemistry 38 (1999): 12041–12051.

    PubMed  CAS  Google Scholar 

  • Thomas B. and Wollmer A. “Cobalt Probing of Structural Alternatives for Insulin in Solution.” Biol. Chem. Hoppe-Seyler 370 (1989): 1235–1244.

    PubMed  CAS  Google Scholar 

  • Wang D., Zeng Z., Hu Y. and Markussen J. “Oligomerization in vitro of the extracellular domain of the insulin receptor by non-covalent interactions is accompnied by increased binding affinity, decreased binding capacity and curvilinear Scatchard plots.” In: Peptides (Y. Du, J.P. Tam and Y. Zhang, eds.), (1993) ESCOM, Leiden, pp. 241–244.

    Google Scholar 

  • Whittingham J.L., Chaudhuri S., Dodson E.J., Moody P.C.E. and Dodson G.G. “X-ray Crystallographic Studies on Hexameric Insulins in the Presence of Helix-Stabilizing Agents, thiocyanate, Methylparaben, and Phenol.” Biochemistry 43 (1995): 15553–15563.

    Google Scholar 

  • Whittingham J.L., Edwards D.J., Antson A.A., Clarkson J.M. and Dodson G.G. “Interactions of Phenol and m-Cresol in the Insulin Hexamer, and Their Effect on the Association Properties of B28 Pro→Asp Insulin Analogues.” Biochemistry 37 (1998): 11516–11523.

    Article  PubMed  CAS  Google Scholar 

  • Williamson K.L. and Williams R.J.P. “Conformational Analysis by Nuclear Magnetic Resonance: Insulin.” Biochemistry 18 (1979): 5966–5972.

    Article  PubMed  CAS  Google Scholar 

  • Wollmer A., Led J.J., Geismar H., Balschmidt P. and Hansen F.B. “The effects of phenolic preservatives on the structure of insulin in solution.” Paper presented at the Second Assisi International Symposium on Advanced Models for the Therapy of Insulin-dependent Diabetes, Assisi, Italy, April 20–23(1986).

    Google Scholar 

  • Wollmer A., Rannefeld B., Johansen B.R., Hejnaes K.R., Balschmidt P. and Hansen F.B. “Phenol-Promoted Structural Transformation of Insulin in Solution.” Biol. Chem. Hoppe-Seyler 368 (1987): 903–911.

    PubMed  CAS  Google Scholar 

  • Wollmer A., Rannefeld B., Stahl J. and Melberg S.G. “Structural Transition in the Metal-Free Hexamer of Protein-Engineered [B13 Gln]Insulin.” Biol. Chem. Hoppe-Seyler 370 (1989): 1045–1053.

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. A. Wollmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Novo Nordisk Pharma GmbH, Mainz, Germany

    Markus Leyck Dieken

  2. Institut für Biochemie, RWTH, Aachen, Germany

    Matthias Federwisch

  3. Hagedorn Research Laboratory, Gentofte, Denmark

    Pierre De Meyts

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Kluwer Academic Publishers

About this chapter

Cite this chapter

Wollmer, A. (2002). T-R Transition. In: Dieken, M.L., Federwisch, M., De Meyts, P. (eds) Insulin & Related Proteins - Structure to Function and Pharmacology. Springer, Dordrecht. https://doi.org/10.1007/0-306-47582-0_7

Download citation

  • DOI: https://doi.org/10.1007/0-306-47582-0_7

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-1-4020-0655-5

  • Online ISBN: 978-0-306-47582-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation