Mapping the bound conformation and protein interactions of microtubule destabilizing peptides by STD-NMR spectroscopy

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 16, 2006, Pages 4279-4282

  Milton, Mark J ^a   Thomas Williamson, R ^a   Koehn, Frank E ^a  

^a WYETH RESEARCH   (United States)

Author keywords

Hemiasterlin; HTI 286; Microtubule destabilization; Saturation transfer difference; STD NMR; Taltobulin; TRNOESY; Tubulin; Tubulin binding

Indexed keywords

ANTINEOPLASTIC AGENT; ESTER; METHYL GROUP; PEPTIDE; PROTON; TALTOBULIN;

ACCURACY; ARTICLE; COMPLEX FORMATION; CRYSTAL STRUCTURE; DRUG CONFORMATION; DRUG DETERMINATION; DRUG PROTEIN BINDING; LEISURE; MICROTUBULE; MOLECULAR STABILITY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PROTEIN ANALYSIS; PROTEIN PROTEIN INTERACTION; QUALITATIVE ANALYSIS; X RAY;

CHEMISTRY, PHARMACEUTICAL; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ESTERS; MAGNETIC RESONANCE SPECTROSCOPY; MICROTUBULE-ASSOCIATED PROTEINS; MICROTUBULES; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROTEIN BINDING; PROTEIN CONFORMATION; SPECTROPHOTOMETRY;

EID: 33745713207     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.05.067     Document Type: Article

References (17)

1. Jordan M.A., and Wilson L. Nat. Rev. Can. 4 (2004) 253
2. Cohen P. Nat. Rev. Drug Disc. 1 (2002) 309
3. Blume-Jensen P., and Hunter T. Nature 411 (2001) 355
4. Talpir R., Benayahu Y., Kashman Y., Pannell L., and Schleyer M. Tetrahedron Lett. 35 (1994) 4453
5. Anderson H.J., Coleman J.E., Anderson R.J., and Roberge M. Cancer Chemother. Pharmacol. 39 (1997) 223
6. Ratain M.J., Undevia S., Janisch l., Roman S., Mayer P., Buckwalter M., Foss D., Hamilton B.L., Fisscher J., and Bukowski R.M. Proc. Am. Soc. Clin. Oncol. 22 (2003) 129
7. Lo M.-C., Aulabaugh A., Krishnamurthy G., Kaplan J., Zask A., Smith R., and Ellestad G. J. Am. Chem. Soc. 126 (2004) 9898
8. Mayer M., and Meyer B. J. Am. Chem. Soc. 123 (2001) 6108
9. Meyer B., and Peters T. Angew. Chem., Int. Ed. 42 (2003) 890
10. Herfurth L., Ernst B., Wagner B., Ricklin D., Strasser D.S., Magnani J.L., Benie A.J., and Peters T. J. Med. Chem 48 (2005) 6879
11. Soubias O., and Gawrisch K. J. Am. Chem. Soc. 127 (2005) 13110
12. Zask A., Birnberg G., Cheung K., Kaplan J., Niu C., Norton E., Suayan R., Yamashita A., Cole D., Tang Z., Krishnamurthy G., Williamson R.T., Khafizova G., Musto S., Hernandez R., Annable T., Yang X., Discafani C., Beyer C., Greenberger L., Loganzo F., and Ayral-Kaloustian S. J. Med. Chem. 47 (2004) 4774
13. Yan J., et al. J. Magn. Res. 163 (2003) 270
14. Nunes M., Kaplan J., Wooters J., Hari M., Minnick A.A., May M.K., Shi C., Musto S., Beyer C., Krishnamurthy G., Qui Y., Loganzo F., Ayral-Kaloustian S., Zask A., and Greenberger L.M. Biochemistry 44 (2005) 6844
15. Coleman J.E., Patrick B.O., Andersen R.J., and Rettig S.J. Acta Crystallogr. Sect., C C52 (1996) 1525
16. Ravi M., Zask A., and Rush T.S. Biochemistry 44 (2005) 15871
17. 1 selective values were obtained from a modified T1 experiment in which the second 180° pulse is replaced with a selective pulse. 1D selective-TRNOESY/ROESY experiments were performed on 240:1 ligand to tubulin sample. 2K scans per experiment with an R/NOE mixing time of 200 ms. 1D selective NOESY data collected for the ligand in the absence of protein were performed with a 500 ms mixing time. Molecular modeling was performed using InsightII/Discover-3 (Accelerys) software. Restraints were applied as a square-well potential function; the upper limit of the function was set at 6 Å. The X-ray structure of hemiasterlin was modified and used in a pseudorandomization protocol (300 ps dynamics at 1000 K) then the structure was subjected to restrained simulated annealing to 10 K then minimized and saved. A total of 10 structures were generated to cover the conformational space.