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Protein/Ligand Interactions

We are using NMR experiments (e.g., transferred nuclear Overhauser effect (trNOESY), water LOGSY, and saturation transfer difference spectroscopy) to experimentally screen for the binding activity of small molecules to:

  1. Develop detection reagents for Clostridial neurotoxins, anthrax proteins, and Yersinia pestis proteins, in collaboration with Rod Balhorn, (Cosman et al., 2002, Chem. Res. Toxicol. 15, 1218-1228).
  2. Study the interactions between the estrogen receptor protein and heterocyclic amines (food mutagens), in collaboration with Brian Bennion, Kris Kulp, Felice Lightstone, and Jim Felton.
  3. Develop SHALS (synthetic high affinity ligands) radiotherapeutics for binding with high specificity to HLA-DR10, which is a non-Hodgkin's lymphoma cell receptor, in collaboration with Rod Balhorn and Drs. Gerry and Sally DeNardo at the UC Davis Cancer Center.
  4. Develop reagents that will be able to detect SUMOlyation in vivo, in collaboration with Rod Balhorn and Hsing-Jien Kung at the UC Davis Cancer Center.

We have also characterized the dynamics, at multiple time scales, of apo and holo cellular retinoic acid binding protein I (CRABPI) (Krishnan et al., 2000, Biochemistry 39, 9119-9129).

Related Links

References

Krishnan, V.V, Sukumar, M., Gierasch, L. M. and Cosman, M. (2000) "Dynamics of cellular retinoic acid binding protein I (CRABPI) on multiple time scales with implications for ligand binding," Biochemistry, 39, 9119-9129.

Cosman, M., Lightstone, F. C., Krishnan, V. V., Zeller, L., Prieto, M. C., Roe, D. C. and Balhorn, R. (2002) "Screening Mixtures of Small Molecules for Binding to Multiple Sites on the Surface of Tetanus Toxin C Fragment by Bioaffinity NMR." Chem. Res. Toxicol. 15, 1218-1228. (Cover)

Cosman, M., Krishnan, V. V. and Balhorn R. (2004) "Application of NMR Methods to identify detection reagents for use in the development of robust nanosensors, in Protein Nanotechnology: Protocols, Instrumentation and Applications" (Tuan Vo-Dinh, Ed.) Human Press, Totowa, NJ, 141-163.

Contact: Kris Kulp [bio], 925-422-6351, kulp2@llnl.gov

 
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The surface of the crystal structure of the tetanus toxin C fragment (TetC, pdb access code 1A8D) is shown with doxorubicin and Ser-Gln-Asn-Tyr-Pro-Ile-Val computationally docked into sites 1 and 2, respectively. By synthetically inking these two compounds together, a new compound that has both higher affinity and specificity for the target protein can be rationally designed. (Cosman et al. 2002, Chem. Res. Toxicol. 15, 1218-1228)