Template Based Design of Anti-Metastatic Drugs from the Active Conformation of Laminin Peptide 11
Abstract
We made significant advances in elucidating the structure of the peptide 11 binding domain of LBP. Phage display studies indicated that three sequence domains in the mid and C-terminal domains are involved. Homology modeling the LBP using the crystal structure of bacterial 52 allowed us to obtain an idea of the overall fold of LBP. Structural studies of LBP require that it is expressed in a recombinant system. We have accomplished this for the full length protein and several fragments. Unfortunately, fragments including the C-terminal domain were not folded well, and the full length rLBP was not stable for sufficient time in solution for NMR structure determination. Therefore, we have started to work on structure determination by X-ray crystallography. Synthesis of the candidate 16 YIGSR mimetic was accomplished but was so inefficient that we have switched to an alternative mimetic structure. LBP was shown to have sulfhydryl oxidase activity, leading us to compare the bioactivity of peptide 11 monomer and dimer. The most active species was found to be the dimer. Several lines of evidence indicate that there is an induced conformational change upon YIGSR binding to LBP. Therefore the bound conformation of the peptide is required for mimetic design.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2002
- Accession Number
- ADB282098
Entities
People
- Jean R. Starkey
Organizations
- Montana State University