Synthetic site-directed ligands
| Autor: | Allen B. Edmundson, Debra L. Harris, James N. Herron, Xiao-Min He, Edward W. Voss, Kathryn R. Ely |
|---|---|
| Rok vydání: | 1989 |
| Předmět: |
Models
Molecular Stereochemistry Protein Conformation Dimer Peptide Antigen-Antibody Complex Ligands Pentapeptide repeat chemistry.chemical_compound Immunoglobulin Fab Fragments Protein structure X-Ray Diffraction Humans Nucleotide Binding site Autoantibodies chemistry.chemical_classification Binding Sites Chemotactic Factors Ligand Antibodies Monoclonal General Medicine chemistry Biochemistry Immunoglobulin G Endorphins Dinitrophenols Bence Jones Protein |
| Zdroj: | Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 323(1217) |
| ISSN: | 0962-8436 |
| Popis: | Complexes of nucleotides, peptides and arom atic hapten-like compounds with immunoglobulin fragments were studied by X-ray analysis. Alter tri- or hexanucleotides of deoxythymidylate were diffused into triclinic crystals of a Fab (BV04- 01) with specificity for single-stranded DNA, extensive changes were detected throughout the structure of the protein. The Fab co-crystallized with a tri- or pentanucleotide in a different space group (monoclinic), an observation sometimes correlated with alterations in the structure of the ‘native’ protein. Structural analyses of the co-crystals are in progress for direct comparisons with the unliganded Fab. In crystals of a human (Meg) Bence-Jones dimer, synthetic opioid peptides, chemotactic peptides or dinitrophenyl (DNP) derivatives could be diffused into a large conical binding cavity. The conformations of both the ligand and the protein were usually altered during the binding process. At the base of the cavity tyrosine residues could be displaced like trap-doors to permit entry of some opioid peptides and DNP compounds into a deep binding pocket. In co-crystals of the dimer and bis(DNP)lysine, two ligand molecules were bound in tandem, one in the main cavity and the second in the deep pocket. One ligand adopted an extended conformation, with the ε-DNP ring near the floor of the main cavity and the α-DNP group in solvent outside the binding site. There were no significant conformational changes in the protein. In contrast, the second ligand was very compact, with both DNP rings immersed in the deep pocket, and the binding site was expanded to accommodate the oversized ligand. Peptides designed to be specific for the main cavity were incrementally constructed from minimal binding units by M. Geysen, G. Trippick, S. Rodda and their colleagues. A pentapeptide optimized for binding by this method was diffused into a crystal of the dimer and found by Fourier difference analysis to lodge exclusively in the main cavity as predicted. Binding regions in the BV04-01 Fab and the Meg dimer were markedly different in size and shape. The Fab had a groove-type site, in which a layer of sidechains acted like a false floor over regions analogous to the cavity and deep pocket of the Bence-Jones dimer. |
| Databáze: | OpenAIRE |
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