CD Spectroscopy and Structure Prediction of a Transmembrane Protein Region

Despite their functional relevance, little is known about the structures of the strongly hydrophobic transmembrane segments of integral membrane proteins such as the inhibitory glycine receptor [l].This receptor belongs to a class of topologically simple membrane proteins. It forms an anion channel due to the supramolecular association of five monomers, each consisting of four putative transmembrane segments Ml, M2, M3 and M4. M2 is unusually polar and thus thought to be involved in anion conduction. In order to span a membrane, the polar M2 would have to be stabilized by interacting with strongly nonpolar segments. Because it is difficult to crystallize membrane proteins for carrying out high resolution crystal structure determinations, alternative approaches employing for example spectroscopic methods need to be developed to obtain informations about structural features such as of single transmembrane segments

Synthesis of DOTA-conjugated multivalent cyclic-RGD peptide dendrimers via 1,3-dipolar cycloaddition and their biological evaluation: implications for tumor targeting and tumor imaging purposes.

Contains fulltext : 52270.pdf (publisher's version ) (Open Access)This report describes the design and synthesis of a series of alpha(V)beta(3) integrin-directed monomeric, dimeric and tetrameric cyclo[Arg-Gly-Asp-d-Phe-Lys] dendrimers using "click chemistry". It was found that the unprotected N-epsilon-azido derivative of cyclo[Arg-Gly-Asp-d-Phe-Lys] underwent a highly chemoselective conjugation to amino acid-based dendrimers bearing terminal alkynes using a microwave-assisted Cu(I)-catalyzed 1,3-dipolar cycloaddition. The alpha(V)beta(3) binding characteristics of the dendrimers were determined in vitro and their in vivoalpha(V)beta(3) targeting properties were assessed in nude mice with subcutaneously growing human SK-RC-52 tumors. The multivalent RGD-dendrimers were found to have enhanced affinity toward the alpha(V)beta(3) integrin receptor as compared to the monomeric derivative as determined in an in vitro binding assay. In case of the DOTA-conjugated (111)In-labeled RGD-dendrimers, it was found that the radiolabeled multimeric dendrimers showed specifically enhanced uptake in alpha(V)beta(3) integrin expressing tumors in vivo. These studies showed that the tetrameric RGD-dendrimer had better tumor targeting properties than its dimeric and monomeric congeners