Chemical inducers of dimerization: The atomic structure of FKBP12-FK1012A-FKBP12

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 1, 1998, Pages 1-6

  Schultz, L Wayne ^a   Clardy, Jon ^a  

^a Department of Molecular Biology and Genetics   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FK 1012A; FK BP12; LIGAND; PROTEIN; UNCLASSIFIED DRUG;

ARTICLE; ATOM; CHEMICAL STRUCTURE; CONTROLLED STUDY; DIMERIZATION; DRUG CONFORMATION; DRUG DESIGN; HYDROGEN BOND; MOLECULE; NONHUMAN; PROTEIN CONFORMATION; PROTEIN DOMAIN; PROTEIN PROTEIN INTERACTION;

DIMERIZATION; IMMUNOPHILINS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; TACROLIMUS; TACROLIMUS BINDING PROTEINS;

EID: 0032488619     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)10195-0     Document Type: Article

References (13)

1. 1. (a) Heldin, C. H. Cell 1995, 80, 213;
2. (b) Austin, D. J.; Crabtree, G. R.; Schreiber, S. L. Chem. Biol. 1994, 1, 131.
3. 2. Clackson, T.; Wells, J. A. Science 1995, 267, 383.
4. 3. (a) Spencer, D. M.; Wandless, T. J.; Schreiber, S. L.; Crabtree, G. R. Science 1993, 262, 1019;
5. (b) Diver, S. T.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 5106.
6. 4. Blau, C. A.; Peterson, K. R.; Drachman, J. G.; Spencer, D. M. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 3076.
7. 1 with a = 133.59(2), b = 40.51(2), c = 93.00(2) Å. The asymmetric unit consists of one half of an FKBP12-FK1012A-FKBP12 dimer and one unliganded FKBP12. Intensity data were collected on a SDMS Mark II area and a rotating anode copper source and gave 15896 unique reflections (91% completeness, Rsym 4.6%). The structure was solved by molecular replacement techniques. Rigid body refinement (X-PLOR, 10-3.5 Å data with |Fo| > 2σ) produced an initial R of 38.6%. Simulated annealing with slow cooling and conjugate gradient positional refinement to 3.0 Å resolution reduced the R to 21.9%. Maps (2|Fo|-|Fc| and |Fo|-Fc|) were used to manually adjust the model. After further postional refinement and adjustment to 2.5 Å resolution, the ligand was fit unambiguously into 3σ density in the |Fo|-|Fc| map. The final model contains half an FKBP12-FK1012A-FKBP12 complex, an unliganded FKBP12, and 176 water molecules and has R of 17.3% for all |Fo| > 2σ data in the resolution range 8-2.0 Å. The rms deviations from ideality are 0.01 Å and 2.8° for bond lengths and bond angles, respectively. Data have been deposited with the Protein Data Bank.
8. 6. Van Duyne, G. D.; Standaert, R. F.; Karplus, P. A.; Schreiber, S. L.; Clardy, J. Science 1991, 251, 839.
9. 7. Ikeda, Y.; Schultz, L. W.; Clardy, J. Schreiber, S. L. J. Am. Chem. Soc. 1994, 116, 4143.
10. 8. (a) Griffith, J. P.; Kim, J. L.; Kim, E. E.; Sintchak, M. D.; Thomson, J. A.; Fitzgibbon, M. J.; Fleming, M. A.; Caron, P. R.; Hsiao, K.; Navia, M. A. Cell 1995, 82, 507.
11. (b) Kissinger, C. R.; Parge, H. E.; Knighton, D. R.; Lewis, C. T.; Pelletier, L. A.; Tempszyk, A.; Kalish, V. J.; Tucker, K. D.; Showalter, R. E.; Moomaw, E. W.; Gastinel, L. N.; Habuka, N.; Chen, X.; Maldonado, F.; Barker, J. E.; Bacquet, R.; Villafranca, J. E. Nature 1995, 378, 641.
12. 9. Kossiakoff, A. A.; Sintchak, M. D.; Shpungin, J.; Prest, L. G. Proteins 1992, 12, 223.
13. 10. Atwell, S.; Ultsch, M.; De Vos, A. M.; Wells, J. A. Science 1997, 278, 1125.