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Complex of rat transthyretin with tetraiodothyroacetic acid refined at 2.1 and 1.8 Å resolution.

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The crystal structure of rat transthyretin (rTTR) complex with 3,5,3' ,5' -tetraiodothyroacetic acid (T4Ac) was determined at 1.8 Å resolution with low temperature synchrotron data collected at CHESS. The structure was refined to R = 0.207 and Rfree= 0.24 with the use of 8-1.8 Å data. The additional 8000 reflections from the incomplete 2.1-1.8 data shell, included in the refinement, reduced the Rfree index by 1.3%. Structure comparison with the model refined against the complete 8-2.1 Å data revealed no differences in the ligand orientation and the conformation of the polypeptide chain in the core regions. However, the high-resolution data included in the refinement improved the model in the flexible regions poorly defined with the lower resolution data. Also additional sixteen water molecules were found in the difference map calculated with the extended data. The structure revealed both forward and reverse binding of tetraiodothyroacetic acid in one binding site and two modes of forward ligand binding in the second site, with the phenolic iodine atoms occupying different sets of the halogen binding pockets.
Physical description
  • 1. Jorgensen, E.C. (1978) Thyroid hormones and analogues. II. Structure-activity relationships; in Hormonal Proteins and Peptides (Li, C.H., ed.) vol. 6, pp. 108-204, Academic Press, New York.
  • 2. Hutinec, A., Ziogas, A., & Rieker, A. (1996) Non-natural phenolic acids. Synthesis and application in peptide chemistry. Amino Acids 1996, 345-366.
  • 3. De la Paz, P., Burridge, J.M., Oatley, S.J. & Blake, C.C.F. (1992) Multiple modes of binding of thyroid hormones and other iodothyronines to human plasma transthyretin; in The Design of Drugs to Macromolecular Targets (Beddell, C.R., ed.) pp. 120-172, John Willey & Sons Ltd.
  • 4. Hamilton, J.A., Steinrauf, L.K., Braden, B.C., Liepnieks, J., Benson, M.D., Holmgren, G., Sandgren, O. & Steen, L. (1993) The X-ray crystal structure refinements of normal human transthyretin and theamyloidogenic Val30Met variant to 1.7 Å resolution. J. Biol. Chem. 268, 2416-2424.
  • 5. Blake, C.C.F., Geisow, M.J., Oatley, S.J., Rerat, B., & Rerat, C. (1978) Structure of prealbumin: Secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 Å. J. Mol. Biol. 121, 339-356.
  • 6. Wojtczak, A., Cody, V., Luft, J. & Pangborn, W. (1996) Structures of human transthyretin complexed with thyroxine at 2.0 Å resolution and 3’,5’-dinitro-N-acetyl-L-thyronine at 2.2 Å resolution. Acta Crystallogr. D52, 758-765.
  • 7. Peterson, S.A., Klabunde, T., Lashuel, H.A., Purkey, H., Sacchettini, J.C. & Kelly, J.W. (1998) Inhibiting thransthyretin conformational changes that lead to amyloid fibril formation. Proc. Natl. Acad. Sci. U.S.A. 95, 12956-12960.
  • 8. Petrassi, H.M., Klabunde, T., Sacchettini, J. & Kelly, J.W. (2000) Structure-based design of N-phenyl phenoxazine transthyretin amyloid fibril inhibitors. J. Am. Chem. Soc. 122, 2178-2192.
  • 9. Wojtczak, A. (1997) Crystal structure of rat transthyretin at 2.5 Å resolution: First report on a unique tetrameric structure. Acta Biochim. Polon. 44, 505-518.
  • 10. Wojtczak, A., Cody, V., Luft, J. & Pangborn, W. (2001) Structure of rat transthyretin (rTTR) complex with thyroxine at 2.5 Å resolution: First non-biased insight into thyroxine binding reveals different hormone orientation in two binding sites. Acta Crystallogr. D57, 1061-1070.
  • 11. Pages, R.A., Robbins, J. & Edelhoch, H. (1973) Binding of thyroxine and thyroxine analogs to human serum prealbumin. Biochemistry 12, 2773-2779.
  • 12. Ferguson, R.N., Edelhoch, H., Saroff, H.A. & Robbins, J. (1975) Negative cooperativity in the binding of thyroxine to human serum prealbumin. Biochemistry 14, 282-289.
  • 13. Wojtczak, A., Neumann, P., Muzioł, T. & Cody, V. (2001) Novel binding mode of tetraiodothyroacetic acid in transtryretin. Acta Crystallogr. D. Submitted.
  • 14. Cody, V., Hazel, J., Langs, D.A. & Duax, W.L. (1977) Molecular structure of thyroxine analogs. Crystal structure of 3,3’,5-triiodothyroacetic and 3,5,3’,5;-tetraiodothyroacetic acid N-diethanolaminne (1:1) complexes. J. Med. Chem. 20, 1628-1631.
  • 15. Nowak, W. & Wojtczak, A. (1997) Quantum chemical modelling of thyroid hormone analogues. J. Mol. Struct. (Theochem) 419, 121-131.
  • 16. Kleywegt, G.J. & Jones, T.A. (1996) xdlMAPMAN and xdlDATAMAN - programs for reformatting, analysis and manipulations of biomacromolecular electron-density maps and reflections data sets. Acta Crystallogr. D52, 826-828.
  • 17. Guo, D.Y., Blessing, R.H. & Langs, D.A. (2000) On globbicit: of low-resolution protein structures. Acta Crystallogr. D56, 451-457.
  • 18. Kleywegt, G.J. (2000) Validation of protein crystal structures. Acta Crystallogr. D56, 249-265.
  • 19. Dodson, E., Kleywegt, G.J. & Wilson, K. (1996) Report of a workshop on the use of statistical validators in protein X-ray crystallography. Acta Crystallogr. D52, 228-234.
  • 20. Brunger, A. (1992) XPLOR Version 3.1. A System for X-ray Crystallography and NMR. Yale University Press, New Haven.
  • 21. Brünger, A.T., Adams, P.D., Clore, G.M., DeLano, W.L., Gros, P., Grosse-Kunstleve, R.W., Jiang, J.-S., Kuszewski, J., Nilges, M., Pannu, N.S., Read, R.J., Rice, L.M., Simonson, T. & Warren, G.L. (1998) Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr. D54, 905-921.
  • 22. Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard, M. (1991) Improved methods for building proteins models in electron density maps and the location of errors in these models. Acta Crystallogr. A47, 110-119.
  • 23. Kleywegt, G.J. (1996) Use of non-crystallographic symmetry in protein structure refinement. Acta Crystallogr. D52, 842-857.
  • 24. Wojtczak, A., Neumann, P. & Cody, V. (2001) Structure of a new polymorphic monoclinic form of human transthyretin at 3 Å resolution reveals a mixed complex between unliganded and T4-bound tetramers of TTR. Acta Crystallogr. D57, 957-967.
  • 25. Evans, S.V. (1993) SETOR: Hardware lighted three-dimensional solid model representations of macromolecules. J. Mol. Graph 11, 134-138.
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