GRAFTER: a computational aid for the design of novel proteins.
The GRAFTER suite of programs provides geometric search and evaluation functions that simplify and automate the process of identifying the best scaffolds for a particular structural motif. Three application of the GRAFTER suite are presented. Potential grafts between lambda repressor and 434 repressor were identified that should change the DNA binding specificity of these repressors. These results are compared with site-directed mutagenesis experiments that have been shown to alter repressor-DNA binding specificity. Next, 26 loops from antibody structures were grouped into families of similar structure. Grafts of antibody loops onto a pre-existing scaffold are an essential component of antibody humanization. Finally, interleukin (IL)-4 was searched as a scaffold that might accept the graft of a five residue epitope from human growth hormone (hGH). The existence of a crystal structure of the hGH-hGH receptor complex, extensive mutagenesis studies of the hGH residues that contribute to the energetics of ligand-receptor interactions and the gross structural homology between hGH and IL-4 make this an appealing computational target. The approach presented here could aid the development of novel enzymes and binding proteins.
Hearst
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DP
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
Cohen
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FE
D000906:Antibodies / Q000737:chemistry; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000737:chemistry; D015847:Interleukin-4 / Q000737:chemistry; D008958:Models, Molecular; D015202:Protein Engineering / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012984:Software
D000906:Antibodies; D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4