Boehringer Mannheim award lecture 1995. La conference Boehringer Mannheim 1995. De novo design of alpha-helical proteins: basic research to medical applications.
The two-stranded alpha-helical coiled-coil is a universal dimerization domain used by nature in a diverse group of proteins. The simplicity of the coiled-coil structure makes it an ideal model system to use in understanding the fundamentals of protein folding and stability and in testing the principles of de novo design. The issues that must be addressed in the de novo design of coiled-coils for use in research and medical applications are (i) controlling parallel versus antiparallel orientation of the polypeptide chains, (ii) controlling the number of helical strands in the assembly (iii) maximizing stability of homodimers or heterodimers in the shortest possible chain length that may require the engineering of covalent constraints, and (iv) the ability to have selective heterodimerization without homodimerization, which requires a balancing of selectivity versus affinity of the dimerization strands. Examples of our initial inroads in using this de novo design motif in various applications include: heterodimer technology for the detection and purification of recombinant peptides and proteins; a universal dimerization domain for biosensors; a two-stage targeting and delivery system; and coiled-coils as templates for combinatorial helical libraries for basic research and drug discovery and as synthetic carrier molecules. The universality of this dimerization motif in nature suggests an endless number of possibilities for its use in de novo design, limited only by the creativity of peptide-protein engineers.
Hodges
R S
RS
Department of Biochemistry, University of Alberta, Edmonton, Canada.
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001671:Biochemistry / Q000266:history; D015374:Biosensing Techniques; D002170:Canada; D002627:Chemistry, Physical; D003553:Cystine / Q000737:chemistry; D019281:Dimerization; D015195:Drug Design; D049673:History, 20th Century; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry; D007769:Lactams / Q000737:chemistry; D016350:Leucine Zippers; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011955:Receptors, Drug / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013698:Templates, Genetic
D000596:Amino Acids; D018796:Immunoconjugates; D007769:Lactams; D008024:Ligands; D011955:Receptors, Drug; D011994:Recombinant Proteins; D003553:Cystine